Biochemical Pharmacology

Sulfated glycolipid PG545 induces endoplasmic reticulum stress and augments autophagic flux by enhancing anticancer chemotherapy efficacy in endometrial cancer

The sulfated glycolipid PG545 shows promising antitumor activity in various cancers. This study was conducted to explore the effects and the mechanism of PG545 action in endometrial cancer (EC). PG545 exhibited strong synergy as assessed by the Chou-Talalay-Method in vitro when combined with cisplatin, or paclitaxel in both type I (Hec1B) and type II (ARK2) EC cell lines. While PG545 showed antitumor activity as monotherapy, a combination of PG545 with paclitaxel and cisplatin was highly effective in reducing the tumor burden and significantly prolonged survival of both Hec1B and ARK2 xenograft bearing mice. Mechanistically, PG545 elicits ER stress as an early response with resultant induction of autophagy. Our data demonstrated an increase in pERK, Bip/Grp78, IRE1α, Calnexin and CHOP/GADD153 within 6-24 hrs of PG545 treatment in EC cells. In parallel, PG545 also blocked FGF2 and HB-EGF mediated signaling in EC cells. Moreover, melatonin-mediated ER stress inhibition reduced PG545-mediated autophagy and PG545 in combination with cisplatin further heightened this stress response. Collectively these data indicate that PG545 exhibits strong synergistic effects with chemotherapeutics in vitro and showed promising antitumor activity in vivo. Our preclinical data indicates that in future studies PG545 can be a useful adjunct to chemotherapy in endometrial cancer.

ATR-mediated phosphorylation of RIPK1 inhibits DNA damage-induced necroptosis

Necroptosis induced by DNA damage during chemotherapy is a significant and effective treatment strategy for epithelial ovarian cancer. Ataxia telangiectasia and rad3-related protein (ATR), a key kinase in DNA damage checkpoints, initiates repair by transmitting damage signals to effectors. However, persistent DNA damage may result in cell death. The mechanisms by which ATR regulates necroptosis remain incompletely understood. In this study, we demonstrated that ATR binds to receptor-interacting serine/threonine-protein kinase 1 (RIPK1) and inhibits its activation, thereby suppressing RIPK1-dependent necroptosis triggered by DNA damage. Mechanistically, ATR directly inhibited RIPK1 and downstream necrosome formation through Ser335 phosphorylation following DNA damage, thereby attenuating RIPK1-dependent necroptosis. In the case of the S335A mutation, RIPK1 repression was relieved, leading to enhanced downstream necroptosis. Furthermore, RIPK1 knockout with complementation of wild-type or S335A mutation in ovarian cancer cell lines revealed that ATR phosphorylation of RIPK1 at S335 promoted chemoresistance, while the S335A mutation significantly increased chemosensitivity. This was characterized by heightened necroptosis activation, reduced cell viability, and increased cell death. These findings expand our understanding of the interaction between DNA damage and cell death regulation and may aid in developing therapeutic drugs to enhance DNA damage-induced tumor necroptosis and improve chemosensitivity.

Regression of ovarian cancer xenografts by depleting or inhibiting RLIP

Ovarian cancer (OC) is the most prevalent and deadly cancer of the female reproductive system. Women will continue to be impacted by OC-related morbidity and mortality. Despite the fact that chemotherapy with cisplatin is the main component as the first-line anticancer treatment for OC, chemoresistance and unfavorable side effects are important obstacles to effective treatment. Targets for effective cancer therapy are required for cancer cells but not for non-malignant cells because they are expressed differently in cancer cells compared to normal cells. Targets for cancer therapy should preferably be components that already exist in biochemical and signalling frameworks and that significantly contribute to the development of cancer or regulate the response to therapy. RLIP is an important mercapturic acid pathway transporter that is crucial for survival and therapy resistance in cancers, therefore, we examined the role of RLIP in regulating essential signalling proteins involved in relaying the inputs from upstream survival pathways and mechanisms contributing to chemo-radiotherapy resistance in OC. The findings of our research offer insight into a novel anticancer effect of RLIP depletion/inhibition on OC and might open up new therapeutic avenues for OC therapy.

Verification of fasting-mimicking diet to assist monotherapy of human cancer-bearing models

The efficacy of a single clinical nanodrug for cancer treatment is still unsatisfactory, especially for drug-resistant cancer. Herein, we applied a fasting-mimicking diet (FMD) approach via dietary intervention to assist single clinical nanodrug for breast or ovarian cancer treatments instead of using multi-drug therapies which might cause adverse side effects. Specifically, we adopted Doxil or Abraxane to treat human breast tumor-bearing nude mice and Doxil to treat the human ovarian tumor and drug-resistant ovarian tumor-bearing nude mice under FMD conditions, respectively. According to the results, the FMD condition can promote the cellular uptake and cytotoxicity of a single nanodrug, reduce the ATP level in drug-resistant tumor cells to hinder drug efflux, normalize tumor blood vessels, relieve tumor hypoxia, and increase the accumulation of nanodrugs at tumor sites, thereby enhancing the therapeutic effects on these types of human cancers. Collectively, these results demonstrate that the FMD strategy of significance can become a practical, alternative, and promising assistant for single nanodrug for enhancing cancer therapy and clinical translation.

Paris saponins Ⅶ inhibits glycolysis of ovarian cancer via the RORC/ACK1 signaling pathway

Rhizoma Paridis is a traditional Chinese medicine commonly used for treatment of malignant tumors. Paris saponins Ⅶ (PSⅦ) is one of the components of Rhizoma Paridis, but the role of PSⅦ in glucose metabolism in ovarian cancer remains elucidated. A series of experiments in the current study demonstrated that PSⅦ inhibites glycolysis and promotes cell apoptosis in ovarian cancer cells. Expression levels of glycolysis-related proteins and apoptosis-related proteins were significantly altered by upon treatment with PSⅦ, as determined from western blot analyses. Mechanistically, PSⅦ exerted its anti-tumor effects by targeting the RORC/ACK1 signaling pathway. These findings indicate that PSⅦ inhibits glycolysis-induced cell proliferation and apoptosis through the RORC/ACK1 pathway, supporting its potential development as a candidate chemotherapeutic agent for ovarian cancer.

Inhibition of STX17–SNAP29–VAMP8 complex formation by costunolide sensitizes ovarian cancer cells to cisplatin via the AMPK/mTOR signaling pathway

Ovarian cancer (OC) is the most common gynecological malignancy. Chemotherapy failure is a major challenge in OC treatment. Targeting autophagy is a promising strategy to enhance the cytotoxicity of chemotherapeutic agents. In this study, we found that costunolide (CTD) inhibits autophagic flux and exhibits high therapeutic efficacy for OC treatment in an in vitro model. Mechanistically, CTD inactivates AMPK/mTOR signaling to inhibit autophagy initiation at the early stage and blocks mTORC1-dependent autophagosome-lysosome fusion at the late stage during autophagy by disrupting SNARE complex (STX17-SNAP29-VAMP8) formation, resulting in lethal autophagy arrest in OC cells. Furthermore, CTD sensitizes OC cells to cisplatin (CDDP) by blocking CDDP-induced autophagy both in vitro and in vivo. Together, our data provide novel mechanistic insights into CTD-induced autophagy arrest and suggest a new autophagy inhibitor for effective treatment of OC.

Mechanistic insights of NAC1 nuclear export and its role in ovarian cancer resistance to docetaxel

In this study, we uncovered the nuclear export of nucleus accumbens-associated protein-1 (NAC1) as a novel mechanism involved in ovarian cancer resistance to taxanes, the chemotherapeutic drugs commonly used in treatment of this malignancy. We showed that NAC1, a nuclear factor of the BTB/POZ gene family, has a nuclear export signal (NES) at the N terminus (aa 17-28), and this NES critically contributes to the NAC1 nuclear-cytoplasmic shuttling when tumor cells were treated with docetaxel. Mechanistically, the nuclear-exported NAC1 bound to cullin3 (Cul3) and Cyclin B1 via its BTB and BOZ domains respectively, and the cyto-NAC1-Cul3 E3 ubiquitin ligase complex promotes the ubiquitination and degradation of Cyclin B1, thereby facilitating mitotic exit and leading to cellular resistance to docetaxel. We also showed in in vitro and in vivo experiments that TP-CH-1178, a membrane-permeable polypeptide against the NAC1 NES motif, blocked the nuclear export of NAC1, interfered with the degradation of Cyclin B1 and sensitized ovarian cancer cells to docetaxel. This study not only reveals a novel mechanism by which the NAC1 nuclear export is regulated and Cyclin B1 degradation and mitotic exit are impacted by the NAC1-Cul3 complex, but also provides the nuclear-export pathway of NAC1 as a potential target for modulating taxanes resistance in ovarian cancer and other malignancies.

Galectin-7 promotes cisplatin efficacy by facilitating apoptosis and G3BP1 degradation in cervical cancer

The emergence of chemoresistance in cervical cancer is extremely challenging in chemotherapy. Oxidative stress has emerged as the regulatory factor in drug resistance, but the detailed mechanism is still unknown. Stress granules, are membrane-less ribonucleoprotein-based condensates, could enhance chemoresistance by sequestering proapoptotic proteins inhibition of cell death upon exposure to drug-induced oxidative stress. Galectin-7, a member of galectin family, exerts varied roles in tumor repression or progression in different cancers. However, its role in cervical cancer has not been sufficiently studied. Here, we found that galectin-7 promotes cisplatin (CDDP) induced apoptosis and associates with stress granule-nucleating protein G3BP1 degradation. With the treatment of cisplatin, galectin-7 could enhance apoptosis by upregulating cleaved-PARP1 and the generation of reactive oxygen species (ROS), promoting mitochondrial fission, and reducing mitochondrial membrane potential (MMP). Furthermore, galectin-7 also reduces resistance by facilitating cisplatin-induced stress granules clearance through galectin-7/RACK1/G3BP1 axis. All these data suggested that galectin-7 promotes cisplatin sensitivity, and it would be potential target for potentiating efficacy in cervical cancer chemotherapy.

Inhibition of RUNX1 promotes cisplatin-induced apoptosis in ovarian cancer cells

Runt-related transcription factor 1 (RUNX1), one subunit of core-binding factors in hematopoiesis and leukemia, was highly expressed in ovarian cancer (OC), but the role of RUNX1 in OC is largely unknown. Since we found that high expression of RUNX1 is correlated with poor survival in patients with OC through bioinformatic analysis of TCGA database, we developed RUNX1-knockout clones by CRISPR/Cas9 technique and discovered that RUNX1 depletion could promote cisplatin-induced apoptosis in OC cells, which was further confirmed by RUNX1 knockdown and overexpression. We also proved that RUNX1 could elevate the expression of BCL2. We then examined a total of 32 candidate miRNAs that might mediate the regulation between RUNX1 and BCL2, of which three miRNAs from the miR-17~92 cluster were found to be negatively regulated by RUNX1. Consistently, our analysis of data from TCGA database revealed the negative correlation between RUNX1 and the cluster. We further confirmed that miR-17~92 cluster could enhance cisplatin-induced apoptosis by directly targeting BCL2 3'UTR. Since rescue experiments proved that RUNX1 could repress cisplatin-induced apoptosis by up-regulating BCL2 via miR-17~92 cluster, combining RUNX1 inhibitor Ro5-3335 and cisplatin showed synergic effect in triggering OC cell apoptosis. Collectively, these findings show for the first time that combinational treatment of cisplatin and RUNX1 inhibitor could be used to potentiate apoptosis of ovarian cancer cells, and reveal the potential of targeting RUNX1 in ovarian cancer chemotherapy.

Targeting G6PD reverses paclitaxel resistance in ovarian cancer by suppressing GSTP1

Ovarian cancer is one of the leading causes of mortality in women worldwide. Currently, paclitaxel is one of the most effective chemotherapies. However, resistance to paclitaxel is a major cause of therapy failure and the precise mechanism of paclitaxel resistance remains unclear. In this study, we demonstrated that the oxidative pentose phosphate pathway (PPP) enzyme glucose-6-phosphate dehydrogenase (G6PD) promotes paclitaxel resistance. We showed that G6PD expression was higher in paclitaxel-resistant cancer cells than in their paclitaxel-sensitive counterparts. Furthermore, we demonstrated that suppressing G6PD using shRNA, or an inhibitor, either as single agents or in combination, sensitized paclitaxel-resistant cancer cells to paclitaxel treatment and thereby improving the therapeutic efficacy of paclitaxel. Interestingly, we found that the upregulation of G6PD in paclitaxel-resistant cells was due to the decreased expression of protein arginine methyltransferase 6 (PRMT6), which targets the promoter of G6PD. We further identified that G6PD promotes paclitaxel resistance by regulating the expression of glutathione S-transferase P1 (GSTP1), which confers resistance to chemotherapy by detoxifying several anticancer drugs. Taken together, our results suggest that G6PD is a novel potential target to overcome paclitaxel resistance.

Role of the TLR4-androgen receptor axis and genistein in taxol-resistant ovarian cancer cells

Toll-like receptor 4 (TLR4) is often overexpressed in taxol-resistant cancer cells. Here we used whole-genome transcriptomic analysis to identify 787 upregulated genes in SKOV3 ovarian carcinoma cells that ectopically express TLR4. Using chromatin immunoprecipitation enrichment analysis, we observed that 27.8% of the TLR4-upregulated genes identified were androgen receptor (AR)-regulated genes. Accordingly, AR expression was induced in taxol-resistant SKOV3 cells overexpressing TLR4, whereas depletion of TLR4 by shRNA repressed AR expression. Activation of AR by androgens or silencing of AR using shRNA also regulated expression of AR-related genes. We found that expression of DCDC2, ANKRD18B, ALDH1A1, c14orf105, ITGBL1 and NEB was overexpressed in taxol-resistant cells, suggesting the involvement of these AR-related genes in taxol resistance. Pathway enrichment analysis confirmed that the expression of several upregulated genes enriched in steroid biosynthesis pathways was inducible by androgens, supporting the results of previous studies. We also observed that genistein inhibits AR activation, leading to suppression of AR-driven genes and reduced taxol resistance in ovarian cancer cells. Overall, we identified six TLR4- and AR-regulated genes involved in taxol resistance. Our results reveal that the TLR4/AR axis plays a critical role in taxol resistance and that genistein is a candidate compound to limit chemoresistance and improve cancer treatment in ovarian cancer.

Cytoplasmic expression of EGFR shRNA using a modified T7 autogene-based hybrid mRNA/DNA system induces long-term EGFR silencing and prolongs antitumor effects

Unusual activation or overexpression of epidermal growth factor receptor (EGFR) has been found in various cancers, and therefore down-regulation of EGFR expression is recognized as a promising strategy for cancer treatment. For decades, RNAi has emerged as an effective solution to regulate gene overexpression, but transient effects of exogenous siRNA have limited the development of EGFR-targeting siRNA therapeutics. Recently, we developed T7 autogene-based hybrid mRNA/DNA system as a non-viral vector for shRNA production and reported the feasibility of long-term silencing for RFP expression as a concept of proof. To investigate its therapeutic availability in cancer therapy, we here modified the hybrid system to stably express EGFR shRNA and confirmed the antitumor effects. When autocatalytic production of T7pol protein in cytoplasm was combined with pT7-driven cytoplasmic transcription for EGFR shRNA, a single transfection lead to stable EGFR silencing in SKOV3 cells for more than 13 days. Also, liposomal systemic administration at two-week intervals resulted in significant inhibition of tumor growth in both SKOV3-bearing mice and PDX models, contrast to the conventional siRNA approach. Our results show an efficient strategy to overcome the temporary effects of synthetic EGFR siRNA in cancer treatment and ultimately provide a potential candidate as an anticancer drug.

DIAPH1 facilitates paclitaxel-mediated cytotoxicity of ovarian cancer cells

The chemotherapeutic agent paclitaxel (PTX) selectively binds to and stabilizes microtubule (MTs). Also, the activated formin Diaphanous Related Formin 1 (DIAPH1) binds to MTs and increases its stability. In a recent study, we found that high DIAPH1 levels correlated with increased survival of ovarian cancer (Ovca) patients. A possible explanation for this finding is that Ovca cells with high DIAPH1 levels are more sensitive to PTX. To examine this assumption, in this study the effect of DIAPH1 depletion on PTX-mediated cytotoxicity of OVCAR8 and OAW42 cells was analyzed. Our data showed that down-regulation of DIAPH1 expression decreased PTX sensitivity in both cell lines by reducing apoptosis or necrosis. Analysis of MT stability by Western blotting revealed a decreased concentration of stable, detyrosinated MTs in PTX-treated DIAPH1 knock-down compared to control cells. Also, in fixed metaphase cells the level of stable, detyrosinated spindle MTs decreased in cells with reduced DIAPH1 expression. In vitro analysis with recombinant DIAPH1 protein showed that PTX and DIAPH1 exhibited additive effects on MT-polymerization, showing that also in a cell-free system DIAPH1 increased the effect of PTX on MT-stability. Together, our data strongly indicate that DIAPH1 increases the response of Ovca cells to PTX by enhancing PTX-mediated MT-stability.

FGFR3 phosphorylates EGFR to promote cisplatin-resistance in ovarian cancer

Ovarian cancer is a deadly gynecologic cancer, and the majority of patients with ovarian cancer experience relapse after traditional treatment. Cisplatin (DDP) is a common chemotherapeutic drug for ovarian cancer, but many patients acquire DDP-resistance after treatment with long-term chemotherapy. The mechanisms of drug-resistance in ovarian cancer are not clear, and we thus aim to investigate novel targets for DDP-resistant ovarian cancer. Differential analysis, KEGG pathway enrichment and protein interaction networks were employed to identify the key genes related to DDP-resistance in ovarian cancer. Subsequently, cell viability, apoptosis and migration were measured to assess the effect of fibroblast growth factor receptor 3 (FGFR3) on DDP-resistance. Further, Pearson correlation analysis and co-expression analysis were used to explore the downstream pathways of FGFR3, and the function of FGFR3 and its downstream targets were further demonstrated by in vitro and nude mice experiments. FGFR3 were expressed at high levels in DDP-resistant ovarian cancer cells. FGFR3 silencing suppressed the activation of PI3K/AKT pathway and impeded the drug-resistance and development of tumor cells. Afterwards, we found that FGFR3 was co-expressed with epidermal growth factor receptor (EGFR). FGFR3 overexpression elevated EGFR phosphorylation and activated PI3K/AKT signaling. Furthermore, in nude mice, silencing FGFR3 and inhibiting EGFR phosphorylation were observed to promote the therapeutic effect of DDP. In conclusion, FGFR3 overexpression enhances DDP-resistance of ovarian cancer by promoting EGFR phosphorylation and further activating PI3K/AKT pathway. This study may offer promising targets for DDP-resistant ovarian cancer.

TLR4/IL-6/IRF1 signaling regulates androgen receptor expression: A potential therapeutic target to overcome taxol resistance in ovarian cancer

Ovarian cancer is poorly treatable due, at least in part, to induced drug resistance to taxol- and cisplatin-based chemotherapy. Recent studies showed that ectopic overexpression of toll-like receptor 4 (TLR4) in ovarian cancer cells leads to upregulation of the androgen receptor (AR) and transactivation of taxol resistance genes, thereby causing chemoresistance. In the present study, we examined the signaling pathways involving TLR4 and interleukin 6 (IL-6) that enhance AR expression. Based on transcriptomic analysis, we show that IL-6 functions as a hub gene among the upregulated genes in taxol-treated TLR4-overexpressing ovarian cancer cells. Both the TLR4 activator taxol and IL-6 can induce AKT phosphorylation, whereas TLR4 knockdown or inhibition of the IL-6 signal transducer GP130 abrogates AKT activation. Furthermore, expression of AR and IL-6 is downregulated in TLR4-knockdown, taxol-resistant cells. In addition, TLR4 knockdown inhibits GP130 and IL-6 receptor alpha (IL6Rα) activities, indicating that TLR4 plays a critical role in IL-6 signaling. On the other hand, nuclear translocation of AR is induced by IL-6 treatment, whereas knockdown of endogenous IL-6 reduces AR and TLR4 expression in taxol-resistant ovarian cancer cells. These results indicate that TLR4 and IL-6 play a crucial role in AR gene regulation and function. We also identify interferon regulatory factor 1 (IRF1) as a downstream target of IL-6 signaling and as a regulator of AR expression. Moreover, analysis of clinical samples indicates that high IL-6 expression correlates with poor progression-free survival in ovarian cancer patients treated with taxol. Overall, our findings indicate that the TLR4/IL-6/IRF1 signaling axis represents a potential therapeutic target to overcome AR-based taxol resistance in ovarian cancer.

The role of PICT1 in RPL11/Mdm2/p53 pathway-regulated inhibition of cell growth induced by topoisomerase IIα inhibitor against cervical cancer cell line

Our previous work showed that a podophyllum derivative (D-3F), named 4-N-(2-Amino-3-fluoropyridine) -4-deoxidation-4'-demethylepipofophyllotoxin, inhibits the activity of topoisomerase II (TOPO II) and then results in DNA damage. Also, D-3F increases the expression of p53 to induce cervical cancer HeLa cell apoptosis by enhancing its stability, due to the translocation of RPL11 to interact with Mdm2 and then consequently causing the blockage of the Mdm2-p53 feedback loop. In present study, we further explored the detailed mechanism of the antitumor activity of D-3F against cervical cancer cell line. Firstly, the decreased level of protein interacting with carboxyl terminus 1 (PICT1) in cervical cancer cell lines (HeLa and SiHa) treated with D-3F, exerted its potent inhibitory effect on cellular proliferation, which was dependent on the inhibition of TOPO IIα activity induced by D-3F in vitro. In addition, the downregulation of PICT1 was required to enhancement of p53 stability, resulted from its promoting the nucleoplasmic translocation of RPL11 to bind to Mdm2 following D-3F treatment. Altogether, it demonstrated that the reduction of PICT1 level in HeLa cell line, as well as SiHa exposed to D-3F, a TOPO IIα inhibitor, may play an essential role in the regulation of RPL11/Mdm2/p53 pathway to induce cell apoptosis. Besides, it suggested the potential of this podophyllum derivative (D-3F) as an alternative agent for therapy in cervical cancer.

Decoding YOD1: Insights into tumour regulation and translational opportunities

KCMF1 regulates HRI ubiquitination to inhibit the integrated stress response in ovarian cancer

This study aimed to investigate the biological functions and underlying mechanisms of potassium channel modulatory factor 1 (KCMF1) in ovarian cancer (OC). KCMF1 expression in OC was analyzed using single-cell sequencing, quantitative real-time reverse transcription polymerase chain reaction, immunohistochemistry, and western blot analysis. The effects of KCMF1 on OC progression were evaluated in cell lines and a xenograft mouse model. The effect of KCMF1 on the integrated stress response (ISR) was evaluated by assessing heme-regulated inhibitor (HRI) ubiquitination using Ni-NTA pull-down assays, immunohistochemistry, and western blotting. KCMF1 was highly expressed in OC epithelial cells and was associated with poor prognosis in patients with OC. Overexpression of KCMF1 promoted OC cell proliferation, migration, and invasion and inhibited cell apoptosis. On the other hand, KCMF1 knockdown produced the opposite results and inhibited tumor growth. Knockdown of KCMF1 reduced HRI ubiquitination and promoted the phosphorylation of eukaryotic translation initiation factor 2 subunit alpha (eIF2α), and the expression of activating transcription factor (ATF)4, ATF3, and sestrin 2 (SESN2), while KCMF1 overexpression produced the opposite results. Additionally, an ISR inhibitor reversed the effects of KCMF1 knockdown on OC cell proliferation, migration, and invasion. Plantainoside D was identified as a novel KCMF1 inhibitor that exhibited potent antitumor activity in OC. Overall, KCMF1 regulates HRI ubiquitination to inhibit ISR, thereby promoting tumor growth and progression in OC.

Roles of TRPM7 in ovarian cancer

Ovarian cancer stands as the prevailing gynecologic malignancy, afflicting over 313,959 individuals annually worldwide, accompanied by more than 207,252 fatalities. Perturbations in calcium signaling contribute significantly to the pathogenesis of numerous cancers, including ovarian cancer, wherein alterations in calcium transporter expression have been reported. Overexpression of TRPM7, a prominent calcium transporter, has been linked to adverse prognostic outcomes in various cancer types. The focus of this comprehensive review centers around delineating the oncogenic role of TRPM7 in cancer development and exploring its therapeutic potential as a target in combating this disease. Notably, TRPM7 fosters cancer invasion, metastasis, and uncontrolled cell proliferation, thereby perpetuating the expansion and reinforcement of these malignant entities. Furthermore, this review takes ovarian cancer as an example and summarizes the "dual-mode" regulatory role of TRPM7 in cancer. Within the domain of ovarian cancer, TRPM7 assumes the role of a harsh tyrant, firmly controlling the calcium ion signaling pathway and metabolic reprogramming pathways.

Cinnamaldehyde suppresses ovarian cancer progression by activating ROS-mediated apoptosis and mitophagy

Cinnamaldehyde (CA), a natural bioactive compound derived from Cinnamomum species, has demonstrated broad-spectrum antitumor activity. However, its therapeutic potential and precise mechanisms in ovarian cancer (OC) remain incompletely elucidated. In this study, we systematically investigated the inhibitory effects of CA on OC and the underlying molecular mechanisms through both in vitro and in vivo approaches. In vitro experiments demonstrated that CA significantly induces reactive oxygen species (ROS) accumulation in OC cells, activates mitochondria-mediated apoptosis, and induces mitochondrial autophagy via the AMPK/ULK1/Beclin1 signaling axis. These synergistic effects collectively lead to significant suppression of OC cell proliferation. In a murine xenograft model of OC, CA administration substantially inhibited the growth of heterotransplanted tumors. Further in vivo analyses revealed a significant increase in the number of apoptotic cells and upregulation of the expression of the autophagy markers LC3B, PINK1, and Parkin in tumor tissues. Concurrently, the expression of the autophagic substrate p62 and the mitochondrial membrane protein TOMM20 decreased. These findings consistently corroborated the cellular mechanisms observed in vitro. This study provides the first evidence that CA suppresses OC progression via ROS-mediated dual mechanisms: apoptosis induction and mitophagy activation. Our results underscore the translational potential of CA as a promising therapeutic candidate and provide a robust experimental foundation for its further development against OC.

RECQL4 as a novel drug target against ovarian cancer

Ovarian cancer is characterized by poor specificity and unfavorable prognosis. Therefore, exploring new mechanisms of ovarian cancer development, identifying specific new targets, and developing effective therapeutic drugs based on these new targets have become the focus of current research. This study collected clinical case tissues from high-grade serous ovarian cancer (HGSC) patients and found that the expression of RecQ-like helicase 4 (RECQL4) was positively correlated with the malignancy of ovarian cancer but negatively correlated with its prognosis. From the chemical library of traditional Chinese medicine and ethnic medicines established by our research group in Guizhou, we screened out an effective target, a fluorinated tanshinone analogue (TC12-1), which can effectively inhibit and bind to RECQL4. In vitro experiments showed that TC12-1 induced apoptosis and inhibited cancer cell invasion and metastasis. Additionally, TC12-1 can induce DNA damage, enhancing replication fork stress and blocking the cell cycle at the S phase in cancer cells. The compound effectively inhibited tumor growth and metastasis in subcutaneous tumor models and in orthotopic ovarian cancer mouse models, showing no significant toxicity to vital organs in tumor animal models. The molecular mechanism of TC12-1 targeting RECQL4 in anti-ovarian epithelial cell carcinoma involves the regulation of key genes such as γ-H2AX, PRPA32, ATM, RAD50, CHK2, P53, P21, Bax, Cyclin E, and CDC2, thereby affecting the cell cycle and DNA replication signaling pathways. The results provide theoretical support for developing specific ovarian cancer therapeutic drugs using RECQL4 as a new target.

FKBP38 expression level dictates paclitaxel resistance via interacting with Bcl-2 in endometrial cancer

Endometrial cancer (EC) is a gynecological malignancy that faces the serious challenge of chemotherapy resistance. Therefore, there is an urgent clinical need to investigate this issue. In this study, we focused on the potential role of FKBP38, a membrane-bound chaperone protein primarily located in the outer mitochondrial membrane. Previous studies have reported reduced FKBP38 expression in ovarian and breast cancer tissues. In this study, we found that FKBP38 expression was significantly decreased in human EC tissues and correlated with poor overall survival in patients receiving chemotherapy. Knockdown of FKBP38 expression in EC cells increased the half-maximal inhibitory concentration of paclitaxel and attenuated the therapeutic response in xenograft models. FKBP38 co-localized and interacted with Bcl-2, and reduced FKBP38 expression inhibited paclitaxel-induced apoptosis by stabilizing mitochondrial function. Importantly, under paclitaxel treatment, FKBP38 knockdown not only increased Bcl-2 expression but also prevented the binding of Bcl-2 to the pro-apoptotic protein, Bad. Collectively, these findings imply that FKBP38 inhibits paclitaxel resistance by interacting with Bcl-2, thereby preserving mitochondrial function. Thus, FKBP38 may serve as a suitable biomarker for targeted antimetabolite therapy in EC.

Identification of Versican as a target gene of the transcription Factor ZNF587B in ovarian cancer

Ovarian cancer is the most lethal malignancy affecting the female reproductive system, with its progression and metastasis being significant contributors to patient mortality. Our previous study identified the zinc finger protein ZNF587B as a potential tumor suppressor that inhibited the proliferation, migration and invasion of ovarian cancer cells, although the underlying mechanism remains elusive. In this study, ZNF587B was demonstrated to bind directly to the promoter region of Versican (VCAN), a high molecular weight chondroitin sulfate glycoprotein, and repress its transcription using Chromatin immunoprecipitation-qPCR (ChIP-qPCR), luciferase reporter assays, and immunofluorescence (IF). Moreover, in vivo and in vitro assays revealed that the effect of ZNF587B knockdown on ovarian cancer proliferation may be mediated through VCAN. Not only that, patients with reduced expression of ZNF587B and increased expression of VCAN exhibit a poorer prognosis. The potential mechanism behind this may involve its impact on the phosphorylation process of AKT.

AHR suppresses cisplatin-induced apoptosis in ovarian cancer cells by regulating XIAP

X-linked inhibitor of apoptosis protein (XIAP) plays a crucial role in cisplatin-induced apoptosis in ovarian cancer, whereas the molecular mechanism of how its expression is dysregulated remains unclear. Here, we report that the aryl hydrocarbon receptor (AHR) acts as a competitive endogenous RNA (ceRNA) of XIAP and can regulate its expression. Overexpression of AHR 3'UTR decreased, while AHR knockdown increased, the cisplatin-induced apoptotic rate in ovarian cancer cells. We also found that one microRNA (miRNA), miR-142-5p, can bind to both AHR and XIAP 3'UTRs and regulate their expression levels. Furthermore, AHR 3'UTR and miR-142-5p can occupy the same Ago2 to form an RNA-induced silencing complex (RISC). In addition, we showed that the effect of AHR overexpression on cisplatin-induced apoptosis could be rescued by either XIAP siRNA or miR-142-5p mimic. Thus, our findings reveal important insights into the molecular mechanism underlying the dysregulation of XIAP in ovarian cancer, indicating that AHR serves as the ceRNA that competes miR-142-5p with XIAP and subsequently affects the platinum-based chemotherapy.

A novel selective FAK inhibitor E2 inhibits ovarian cancer metastasis and growth by inducing cytotoxic autophagy

Ovarian cancer (OC) is the deadliest form of the gynecologic malignancies and effective therapeutic drugs are urgently needed. Focal adhesion kinase (FAK) is overexpressed in various solid tumors, and could serve as a potential biomarker of ovarian cancer. However, there are no launched drugs targeting FAK. Hence, the development of the novel FAK inhibitors is an emerging approach for the treatment of ovarian cancer. In this work, we characterized a selective FAK inhibitor E2, with a high inhibitory potency toward FAK. Moreover, E2 had cytotoxic, anti-invasion and anti-migration activity on ovarian cancer cells. Mechanistically, after treatment with E2, FAK downstream signaling cascades (e.g., Src and AKT) were suppressed, thus resulting in the ovarian cancer cell arrest at G0/G1 phase and the induction of cytotoxic autophagy. In addition, E2 attenuated the tumor growth of PA-1 and ES-2 ovarian cancer subcutaneous xenografts, as well as suppressed peritoneal metastasis of OVCAR3-luc. Furthermore, E2 exhibited favorable pharmacokinetic properties. Altogether, these findings demonstrate that E2 is a selective FAK inhibitor with potent anti-ovarian cancer activities both in vivo and in vitro, offering new possibilities for OC treatment strategies.

WP1066, a small molecule inhibitor of STAT3, chemosensitizes paclitaxel-resistant ovarian cancer cells to paclitaxel by simultaneously inhibiting the activity of STAT3 and the interaction of STAT3 with Stathmin

Paclitaxel is widely used to treat cancer, however, drug resistance limits its clinical utility. STAT3 is constitutively activated in some cancers, and contributes to chemotherapy resistance. Currently, several STAT3 inhibitors including WP1066 are used in cancer clinical trials. However, whether WP1066 reverses paclitaxel resistance and the mechanismremains unknown. Here, we report that in contrast to paclitaxel-sensitive parental cells, the expressions of several pro-survival BCL2 family members such as BCL-2, BCL-XL and MCL-1 are higher in paclitaxel-resistant ovarian cancer cells. Meanwhile, STAT3 is constitutively activated while stathmin loses its activity in paclitaxel-resistant cells. Importantly, WP1066 amplifies the inhibition of cell proliferation, colony-forming ability and apoptosis of ovarian cancer cells induced by paclitaxel. Mechanistically, WP1066, on the one hand, interferes the STAT3/Stathmin interaction, causing unleash of STAT3/Stathmin from microtubule, thus destroying microtubule stability. This process results in reduction of Ac-α-tubulin, further causing MCL-1 reduction. On the other hand, WP1066 inhibits phosphorylation of STAT3 by JAK2, and blocks its nuclear translocation, therefore repressing the transcription of pro-survival targets such as BCL-2, BCL-XL and MCL-1. Finally, the two pathways jointly promote cell death. Our findings reveal a new mechanism wherein WP1066 reverses paclitaxel-resistance of ovarian cancer cells by dually inhibiting STAT3 activity and STAT3/Stathmin interaction, which may layfoundation for WP1066 combined with paclitaxel in treating paclitaxel-resistant ovarian cancer.

Calcium signaling affects migration and proliferation differently in individual cancer cells due to nifedipine treatment

Several papers have reported that calcium channel blocking drugs were associated with increased breast cancer risk and worsened prognosis. One of the most common signs of breast tumors is the presence of small deposits of calcium, known as microcalcifications. Therefore, we studied the effect of dihydropyridine nifedipine on selected calcium transport systems in MDA-MB-231 cells, originating from triple negative breast tumor and JIMT1 cells that represent a model of HER2-positive breast cancer, which possesses amplification of HER2 receptor, but cells do not response to HER2 inhibition treatment with trastuzumab. Also, we compared the effect of nifedipine on colorectal DLD1 and ovarian A2780 cancer cells. Both, inositol 1,4,5-trisphosphate receptor type 1 (IP

Albacarcin V adds EPLIN as a novel and promising target for the treatment of female cancers and pediatric medulloblastoma

Breast and ovarian cancers remain among the most lethal malignancies affecting women worldwide. Despite advances in standard therapies, drug resistance and high relapse rates continue to undermine long-term treatment outcomes. To address these challenges, we re-evaluated five previously identified drug candidates (FLIX1-FLIX5), all of which are effective at nanomolar concentrations in breast and ovarian cancer cell lines. Among them, FLIX3 (Albacarcin V) and FLIX4 exhibited the most potent cytotoxicity, with IC50 values below 50 nM across multiple cell lines. Notably, FLIX3 also exhibited nanomolar-range efficacy in drug-resistant, patient-derived samples from triple-negative breast cancer (TNBC) and ovarian cancer. In a zebrafish model, FLIX3 effectively eliminated cancer cells within its safety window. ATAC-Seq analysis revealed that both compounds induce significant epigenetic alterations. Proteome Integral Solubility Alteration (PISA) and cellular thermal shift assay (CETSA) identified EPLIN (Epithelial Protein Lost in Neoplasm) as the top target of FLIX3 but not FLIX4. EPLIN was previously identified as the primary target of FLIX5. Its re-emergence as the dominant target of FLIX3 highlights its potential as a broadly applicable therapeutic target. Collectively, these findings support the continued development of EPLIN-targeting compounds as promising agents for treating aggressive and drug-resistant breast and ovarian cancers.

Promoting tumor cell secretion of IL18 to induce reprogramming of tumor-associated macrophages – The novel anticancer mechanism of anlotinib in ovarian cancer

Ovarian cancer represents a formidable challenge to female reproductive health, mainly due to a marked propensity for intraperitoneal implant metastasis, as well as a lack of effective therapeutic strategies. Anlotinib, a multi-targeted receptor tyrosine kinase inhibitor, has demonstrated anti-tumor effects across various tumors and promising clinical outcomes in ovarian cancer. However, the underlying molecular mechanisms of anlotinib on tumor-associated macrophages (TAMs) within the ovarian tumor microenvironment have not been completely elaborated yet. In this study, we demonstrated that anlotinib suppressed the proliferation, migration, and invasion ability of ovarian cancer cell line ID8 through in vitro experiments. By co-culturing ovarian cancer cells with human mononuclear macrophage THP-1 or murine (RAW264.7) monocyte-derived macrophages, we observed that anlotinib promoted M1 macrophage polarization while simultaneously inhibiting M2 phenotype polarization of TAMs. Further in vitro experimentation revealed that anlotinib polarized TAMs to M1 macrophages by upregulating the expression of interleukin 18. Finally, we validated the antitumor efficacy of anlotinib in vivo and its ability to reprogram TAMs using an orthotopic ovarian cancer model established with the murine ovarian cancer cell line ID8.

CAR-T therapy for ovarian cancer: Recent advances and future directions

Ovarian cancer (OC) is a common gynecological tumor with high mortality, which is difficult to control its progression with conventional treatments and is prone to recurrence. Recent studies have identified OC as an immunogenic tumor that can be recognized by the host immune system. Immunotherapy for OC is being evaluated, but approaches such as immune checkpoint inhibitors have limited efficacy, adoptive cell therapy is an alternative therapy, in which CAR(chimeric antigen receptor)-T therapy has been applied to the clinical treatment of hematological malignancies. In addition, CAR-NK and CAR-macrophage (CAR-M) have also shown great potential in the treatment of solid tumors. Here, we discuss recent advances in preclinical and clinical studies of CAR-T for OC treatment, introduce the efforts made by researchers to modify the structure of CAR in order to achieve effective OC immunotherapy, as well as the research status of CAR-NK and CAR-M, and highlight emerging therapeutic opportunities that can be utilized to improve the survival of patients with OC using CAR-based adoptive cell therapy.

Gambogic acid induces GSDME dependent pyroptotic signaling pathway via ROS/P53/Mitochondria/Caspase-3 in ovarian cancer cells

Gambogic acid (GA) is a naturally active compound extracted from the Garcinia hanburyi with various anticancer activities. However, whether GA induces pyroptosis (a newly discovered inflammation-mediated programmed cell death mechanism) in ovarian cancer (OC) has not yet been reported. This study revealed that GA treatment reduced cell viability by inducing pyroptosis in OC cell lines. Typical pyroptosis morphological manifestations such as cell swelling with large bubbles and loss of cell membrane integrity, were observed. Cleaved caspase-3 and GSDME-N levels increased after GA treatment, and knocking out GSDME or using a caspase-3 inhibitor could switch GA-induced cell death from pyroptosis to apoptosis, indicating GA induced caspase-3/GSDME-dependent pyroptosis. Furthermore, this research indicated that GA significantly increased reactive oxygen species (ROS) and p53 phosphorylation. OC cells pretreated with ROS inhibitor N-Acetylcysteine (NAC) and the specific p53 inhibitor pifithrin-μ could completely reverse the pyroptosis post-treatment. Elevated p53 and phosphorylated p53 reduced mitochondrial membrane potential (MMP) and Bcl-2, increase the expression of Bax, and damage mitochondria by releasing cytochrome c to activate the downstream pyroptosis pathway. Different doses of GA inhibited tumor growth in ID8 tumor-bearing mice, and high-dose GA increased in tumor-infiltrating lymphocytes CD3, CD4, and CD8 were detected in tumor tissues. Notably, the expressions of GSDME-N, cleaved caspase-3 and other proteins were increased in tumor tissues with high-dose GA groups. These findings demonstrate that GA-treated OC cells could induce GSDME-mediated pyroptosis through the ROS/p53/mitochondria signaling pathway and caspase-3/-9 activation. Thus, GA is a promising therapeutic agent for OC treatment.

Sensitization of cancer cells to paclitaxel-induced apoptosis by canagliflozin

Cancer cells consume more glucose and usually overexpress glucose transporters which have become potential targets for the development of anticancer drugs. It has been demonstrated that selective SGLT2 inhibitors, such as canagliflozin and dapagliflozin, display anticancer activity. Here we demonstrated that canagliflozin and dapagliflozin synergistically enhanced the growth inhibitory effect of paclitaxel in cancer cells including ovarian cancer and oral squamous cell carcinoma cells. Canagliflozin also inhibited glucose uptake via GLUTs. The combination of paclitaxel and WZB117, a GLUT inhibitor, exhibited a strong synergy, supporting the notion that inhibition of GLUTs by canagliflozin may also account for the synergy between canagliflozin and paclitaxel. Mechanistic studies in ES-2 ovarian cancer cells revealed that canagliflozin potentiated paclitaxel-induced apoptosis and DNA damaging effect. Paclitaxel in the nanomolar range elevated abnormal mitotic cells as well as aneuploid cells, and canagliflozin further enhanced this effect. Furthermore, canagliflozin downregulated cyclin B1 and phospho-BUBR1 upon spindle assembly checkpoint (SAC) activation by paclitaxel, and may consequently impair SAC. Thus, paclitaxel disturbed microtubule dynamics and canagliflozin compromised SAC activity, together they may induce premature mitotic exit, accumulation of aneuploid cells with DNA damage, and ultimately apoptosis.

Bavachinin exerts anti-tumor effects by activating TLR4/STING axis-dependent PANoptosis and synergistically enhances chemosensitivity in endometrial cancer

The incidence and mortality rates of endometrial cancer (EC), a malignancy originating from endometrium, have been increasing globally. Currently, there are no effective therapeutic options for patients with recurrent, chemoresistant, and metastatic forms of this disease. Through compound library screening, we identified that bavachinin (BVC) has a killing effect on EC cells. BVC is a bioactive small molecule with potential pharmacological effects derived from the traditional Chinese herb Proralea corylifolia L, but the specific mechanisms are unclear. We first discovered that BVC induces ZBP1 (Z-DNA binding protein 1)-mediated PANoptosis in EC cells, characterized by activating of pyroptosis, apoptosis, and necroptosis. BVC promoted reactive oxygen species (ROS) production, mitochondrial membrane potential (MMP, ΔΨm) collapse, and ATM-CHK2 mediated DNA damage, which activated cGAS-STING pathway in EC cells. Mechanistically, network pharmacology, molecular docking, cellular thermal shift assays (CESTA), and drug affinity responsive target stability (DARTS) experiments revealed that BVC induced PANoptosis in EC cells by directly interacting with toll-like receptor 4 (TLR4), thereby triggering mitochondrial ROS generation, activating the cGAS-STING pathway. Notably, TLR4 knockdown inhibited STING-TBK1-IRF3 pathway and ZBP1-mediated PANoptosis. In addition, low-dose BVC combined with cisplatin increased phosphorylated H2AX expression, suggesting that BVC enhances the sensitivity of EC cells to cisplatin. In vivo studies demonstrated that BVC induced PANoptosis in EC, and BVC in combination with cisplatin had effective anti-tumor effect without injuring vital organs. These novel findings provide compelling evidence to support the clinical application of BVC and PANoptosis-based therapy for treating EC.

Strategies to synergize PD-1/PD-L1 targeted cancer immunotherapies to enhance antitumor responses in ovarian cancer

Anti-programmed cell death 1/programmed cell death ligand 1 (anti-PD-1/PD-L1) antibodies have developed rapidly but exhibited modest activity in ovarian cancer (OC), achieving a clinical response rate ranging from 5.9% to 19%. Current evidence indicate that the establishment of an integrated cancer-immunity cycle is a prerequisite for anti-PD-1/PD-L1 antibodies. Any impairment in this cycle, including lack of cancer antigens release, impaired antigen-presenting, decreased T cell priming and activation, less T cells that are trafficked or infiltrated in tumor microenvironment (TME), and low tumor recognition and killings, will lead to decreased infiltrated cytotoxic T cells to tumor bed and treatment failure. Therefore, combinatorial strategies aiming to modify cancer-immunity cycle and reprogram tumor immune microenvironment are of great interest. By far, various strategies have been studied to enhance responsiveness to PD-1/PD-L1 inhibitors in OC. Platinum-based chemotherapy increases neoantigens release; poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) improve the function of antigen-presenting cells and promote the trafficking of T cells into tumors; epigenetic drugs help to complete the immune cycle by affecting multiple steps; immunotherapies like anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) antibodies reactivate T cells, and other treatment strategies like radiotherapy helps to increase the expression of tumor antigens. In this review, we will summarize the preclinical studies by analyzing their contribution in modifying the cancer immunity cycle and remodeling tumor environment, and we will also summarize recent progress in clinical trials and discuss some perspectives to improve these treatment strategies.

Curcumin reduces paclitaxel resistance in ovarian carcinoma cells by upregulating SNIP1 and inhibiting NFκB activity

The therapeutic activity of paclitaxel against ovarian carcinoma is relatively low due to the frequent occurrence of chemoresistance and disease recurrence. We found earlier that a combination of curcumin and paclitaxel reduces cell viability and promotes apoptosis in paclitaxel-resistant (i.e., taxol-resistant, Txr) ovarian cancer cells. In the present study, we first used RNA sequencing (RNAseq) analysis to identify genes that are upregulated in Txr cell lines but downregulated by curcumin in ovarian cancer cells. The nuclear factor kappa B (NFκB) signaling pathway was shown to be upregulated in Txr cells. Furthermore, based on the protein interaction database BioGRID, we found that Smad nuclear interacting protein 1 (SNIP1) may be involved in regulating the activity of NFκB in Txr cells. Accordingly, curcumin upregulated SNIP1 expression, which in turn downregulated the pro-survival genes Bcl-2 and Mcl-1. Using shRNA-guided gene silencing, we found that SNIP1 depletion reversed the inhibitory effect of curcumin on NFκB activity. Moreover, we identified that SNIP1 enhanced NFκB protein degradation, thereby suppressing NFκB/p65 acetylation, which is involved in the inhibitory effect of curcumin on NFκB signaling. The transcription factor early growth response protein 1 (EGR1) was shown to represent an upstream transactivator of SNIP1. Consequently, we show that curcumin inhibits NFκB activity by modulating the EGR1/SNIP1 axis to attenuate p65 acetylation and protein stability in Txr cells. These findings provide a new mechanism to account for the effects of curcumin in inducing apoptosis and reducing paclitaxel resistance in ovarian cancer cells.

Harmine inhibits ovarian cancer migration and invasion and epithelial-mesenchymal transition (EMT) by inhibiting HDAC7 to restore RECK expression

Harmine, a β-carboline alkaloid derived from Peganum harmala L., exhibits potent anticancer properties, including the suppression of ovarian cancer (OC) cell proliferation and metastasis. However, the underlying molecular mechanisms remain incompletely understood. This study demonstrates that harmine significantly inhibits OC cell migration, invasion, and epithelial-mesenchymal transition (EMT) both in vitro and in vivo. Transcriptome sequencing revealed that harmine downregulates histone deacetylase 7 (HDAC7) while upregulating the reversion-inducing cysteine-rich protein with Kazal motifs (RECK), a tumor suppressor gene frequently silenced in cancers. Functional assays showed that harmine treatment dose- and time-dependently reduced OC cell viability, migration, and invasion, concomitant with elevated RECK expression and suppression of matrix metalloproteinases (MMP2, MMP9) and mesenchymal markers (N-cadherin, Snail, Vimentin), alongside increased E-cadherin levels. Knockdown of RECK abolished these antitumor effects, confirming its pivotal role in harmine-mediated metastasis inhibition. Mechanistically, harmine suppressed HDAC7 expression, and conversely, HDAC7 overexpression reversed harmine's anti-metastatic effects by repressing RECK. Further analysis revealed that HDAC7 binds to transcription factor SP1. Chromatin immunoprecipitation (ChIP) assays confirmed that harmine disrupts this interaction, liberating SP1 to bind the RECK promoter and activate its transcription. Collectively, these findings elucidate a novel HDAC7/RECK/SP1 axis through which harmine exerts its anti-metastatic effects in OC, highlighting its potential as a therapeutic agent for OC treatment.

Patient-derived organoids in ovarian cancer: Current research and its clinical relevance

Regardless of recent advances in cancer treatment, ovarian cancer (OC) patients have had a five-year survival rate of 48% in the last few decades. Diagnosis at the advanced stage, disease recurrence, and lack of early biomarkers are the severe clinical challenges associated with disease survival rate. Identifying tumor origin and developing precision drugs will effectively advance OC patient's treatment. The lack of a proper platform to identify and develop new therapeutic strategies in OC treatment necessitates searching for a suitable model to address tumor recurrence and therapeutic resistance. The development of the OC patient-derived organoid model provided a unique platform to identify the exact origin of high-grade serous OC, drug screening, and the development of precision medicine. This review provides an overview of recent progress in developing patient-derived organoids and their clinical relevance. Here, we outline their uses for transcriptomics and genomics profiling, drug screening, translational study, and their future perspective and clinical outlook as a model to advance OC research that could offer a promising approach for developing precision medicine.

Design and synthesis of novel 7-ethyl-10-fluoro-20-O-(cinnamic acid ester)-camptothecin derivatives as potential high selectivity and low toxicity topoisomerase I inhibitors for hepatocellular carcinoma

A series of new 7-ethyl-10-fluoro-20-O-(cinnamic acid ester)-camptothecin derivatives were synthesized and evaluated for cytotoxicity against four human tumor cell lines including HepG2 (hepatocellular carcinoma), SW480 (colorectal cancer), A2780 (ovarian cancer), and Hucct1 (intrahepatic cholangiocarcinoma). The results of cytotoxic activities in vitro showed that most of the camptothecin derivatives harbor promising cytotoxic activity against tested tumor cell lines. Among them, compound XJS-11 exhibited broad-spectrum inhibitory activities against HepG2, SW480, A2780, and Hucct1 cell lines with IC

H1.0 modulates IL-6 expression and paclitaxel resistance via HDAC5 in ovarian cancer cells

Chemoresistance is a significant challenge and major obstacle to achieving cancer remission during chemotherapy, primarily due to the risk of recurrence and metastasis. This study reveals that linker histone H1.0 plays a crucial role in paclitaxel resistance (TXR) in ovarian cancer cells by regulating Histone deacetylase 5 (HDAC5), which deacetylates core histones and represses gene transactivation. Transcriptomic profile analysis revealed that cytokine signaling networks are enriched pathways that correlate with H1.0 expression. Advanced clustering analysis identified interleukin 6 (IL-6) as a key molecule connecting these enriched H1.0-related pathways. Furthermore, gain- and loss-of-H1.0 expression experiments showed that H1.0 controls IL-6 mRNA and protein expression in ovarian cancer cells. Additionally, our findings indicate that HDAC5 expression is downregulated in SKOV3/Txr cells compared with parental cells. H1.0 silencing in TXR cells increases HDAC5 levels, suggesting an antagonistic effect between H1.0 and HDAC5. Cell viability assays showed that HDAC5 overexpression markedly inhibited cell survival. Furthermore, ectopic HDAC5 overexpression reduced IL-6 mRNA and protein expression, which was increased by H1.0. This effect was associated with reduced H3K9Ac core histone acetylation and decreased NF-κB binding on the IL-6 promoter, as demonstrated by chromatin immunoprecipitation assays. Further analysis revealed that HDAC5 is downregulated in several tumor types. Furthermore, high H1.0 and IL-6 expression, coupled with low HDAC5 levels, was exclusively observed in ovarian carcinoma. Together, our results demonstrate an interplay between H1.0, HDAC5, and IL-6 in modulating paclitaxel resistance in ovarian cancer cells, highlighting new therapeutic targets to overcome chemoresistance.

Caffeic acid phenethyl ester targets ubiquitin-specific protease 8 and synergizes with cisplatin in endometrioid ovarian carcinoma cells

Deubiquitinases (DUBs) mediate the removal of ubiquitin from diverse proteins that participate in the regulation of cell survival, DNA damage repair, apoptosis and drug resistance. Previous studies have shown an association between activation of cell survival pathways and platinum-drug resistance in ovarian carcinoma cell lines. Among the strategies available to inhibit DUBs, curcumin derivatives appear promising, thus we hypothesized their use to enhance the efficacy of cisplatin in ovarian carcinoma preclinical models. The caffeic acid phenethyl ester (CAPE), inhibited ubiquitin-specific protease 8 (USP8), but not proteasomal DUBs in cell-free assays. When CAPE was combined with cisplatin in nine cell lines representative of various histotypes a synergistic effect was observed in TOV112D cells and in the cisplatin-resistant IGROV-1/Pt1 variant, both of endometrioid type and carrying mutant TP53. In the latter cells, persistent G1 accumulation upon combined treatment associated with p27

Gynecological cancer tumor Microenvironment: Unveiling cellular complexity and therapeutic potential