Pharmacological Research

Coptidis rhizoma and berberine as anti-cancer drugs: A 10-year updates and future perspectives

Natural compounds targeting ferroptosis in ovarian cancer: Research progress and application potential

Ovarian cancer (OC) is among the most common malignancies in the female reproductive system, marked by high rates of recurrence and mortality. Conventional chemotherapy, however, faces limitations due to the development of drug resistance, which hinders its effectiveness. Ferroptosis, an atypical form of programmed cell death distinct from autophagy, apoptosis, and necrosis, the relationship with tumors has become a hot research area in cancer studies in recent years. Anticancer therapies that target ferroptosis show strong potential in improving prognosis and counteracting chemotherapy resistance. Natural compounds, as a valuable source of novel targeted anticancer agents, its significant role in inhibiting tumor cell proliferation and metastasis and improving therapeutic sensitivity has been demonstrated in numerous existing studies. This review summarizes a range of natural compounds that target ferroptosis in OC cells, discussing their active components, mechanisms of action, and therapeutic potential, thereby providing useful insights for future targeted therapy and research in OC.

Novel mesothelin-targeted chimeric antigen receptor-modified UNKT cells are highly effective in inhibiting tumor progression

The design of chimeric antigen receptors (CAR) significantly enhances the antitumor efficacy of T cells. Although some CAR-T products have been approved by FDA in treating hematological tumors, adoptive immune therapy still faces many difficulties and challenges in the treatment of solid tumors. In this study, we reported a new strategy to treat solid tumors using a natural killer-like T (NKT) cell line which showed strong cytotoxicity to lyse 15 cancer cell lines, safe to normal cells and had low or no Graft-versus-host activity. We thus named it as universal NKT (UNKT). In both direct and indirect 3D tumor-like organ model, UNKT showed efficient tumor-killing properties, indicating that it could penetrate the microenvironment of solid tumors. In mesothelin (MSLN)-positive tumor cells (SKOV-3 and MCF-7), MSLN targeting CAR modified-UNKT cells had enhanced killing potential against MSLN positive ovarian cancer compared with the wild type UNKT, as well as MSLN-CAR-T cells. Compared with CAR-T, Single-cell microarray 32-plex proteomics revealed CAR-UNKT cells express more effector cytokines, such as perforin and granzyme B, and less interleukin-6 after activation. Moreover, our CAR-UNKT cells featured in more multifunctionality than CAR-T cells. CAR-UNKT cells also demonstrated strong antitumor activity in mouse models of ovarian cancer, with the ability to migrate and infiltrate the tumor without inducing immune memory. The fast-in and -out, enhanced and prolonged tumor killing properties of CAR-UNKT suggested a novel cure option of cellular immunotherapy in the treatment of MSLN-positive solid tumors.

Cancer and SOX proteins: New insight into their role in ovarian cancer progression/inhibition

Transcription factors are potential targets in disease therapy, particularly in cancer. This is due to the fact that transcription factors regulate a variety of cellular events, and their modulation has opened a new window in cancer therapy. Sex-determining region Y (SRY)-related high-mobility group (HMG) box (SOX) proteins are potential transcription factors that are involved in developmental processes such as embryogenesis. It has been reported that abnormal expression of SOX proteins is associated with development of different cancers, particularly ovarian cancer (OC). In the present review, our aim is to provide a mechanistic review of involvement of SOX members in OC. SOX members may suppress and/or promote aggressiveness and proliferation of OC cells. Clinical studies have also confirmed the potential of transcription factors as diagnostic and prognostic factors in OC. Notably, studies have demonstrated the relationship between SOX members and other molecular pathways such as ST6Ga1-I, PI3K, ERK and so on, leading to more complexity. Furthermore, SOX members can be affected by upstream mediators such as microRNAs, long non-coding RNAs, and so on. It is worth mentioning that the expression of each member of SOX proteins is corelated with different stages of OC. Furthermore, their expression determines the response of OC cells to chemotherapy. These topics are discussed in this review to shed some light on role of SOX transcription factors in OC.

Deficiency of tumor-expressed B7-H3 augments anti-tumor efficacy of anti-PD-L1 monotherapy rather than the combined chemoimmunotherapy in ovarian cancer

As a high mortality gynecological malignancy, most ovarian cancer patients experience refractory to standard chemotherapy, current immunotherapy or chemoimmunotherapy in clinic and clinical trials. The underlying mechanisms and biomarkers predictive of response for patient selection is quite urgent. In this study, we found that the level of tumor-expressed B7-H3 is positively correlated with the poorer prognosis in ovarian cancer patients. Therapeutically, in syngeneic mouse model of ovarian cancer, deficiency of tumor-expressed B7-H3 significantly potentiates the anti-tumor efficacy of paclitaxel or PD-L1 blockade monotherapy. However, combination of paclitaxel plus anti-PD-L1 has no synergistic effects than PD-L1 blockade monotherapy. Mechanistically, deficiency of tumor-expressed B7-H3 attenuates inflammatory cytokine IL-6 production, upregulates type I interferon (IFN) expression and increases paclitaxel-induced tumor cells apoptosis via caspase 3 activation pathway, resulting in reprogramming the tumor microenvironment including increasing the infiltration of effector T lymphocytes and decreasing the recruitment of Ly6G

HPV vaccination and malignancy risks beyond cervical cancer: A retrospective global cohort study

While HPV vaccination is well established for the prevention of cervical cancer, its broader oncological effects remain insufficiently characterized. Emerging evidence suggests potential protective effects against non-cervical malignancies; however, comprehensive long-term data are limited. We conducted a global, retrospective cohort study utilizing electronic health records from the TriNetX network. Individuals vaccinated against HPV at age 8 years or older were propensity score-matched to unvaccinated controls. Outcomes included the incidence of malignancies in the head-and-neck, gastrointestinal, anogenital, neuronal, and hematologic systems, as well as all-cause mortality, assessed over 8- and 20-year follow-up periods. Kaplan-Meier survival analysis and hazard ratios (HRs) were employed. HPV vaccination was associated with significant reductions in the risk of hypopharyngeal and laryngeal carcinomas (8-year HR: 0.19; 95 % CI: 0.057-0.631; p = 0.0025; 20-year HR: 0.227; 95 % CI: 0.067-0.764; p = 0.0092) and leukemia (8-year HR: 0.461; p = 0.0035; 20-year HR: 0.443; p = 0.0019). No significant protection was observed for rectal, anal, oral cavity, or prostate cancers. All-cause mortality was reduced by nearly half among vaccinated individuals (8-year HR: 0.543; 20-year HR: 0.536; both p < 0.0001). Beyond epithelial malignancies, HPV vaccination may confer systemic cancer protection, particularly in hematologic and potentially neuronal tissues. These findings suggest a broader biological impact of HPV vaccination than previously recognized and underscore the need for mechanistic studies investigating HPV's oncogenic pathways. If validated, these results could prompt the expansion of vaccination strategies to encompass broader indications and wider population coverage.

DOC2B is a negative regulator of Wnt/β-catenin signaling pathway in cervical cancer

DOC2B is a ubiquitously expressed isoform of the double C-2 protein family that requires Ca

A small-molecule inhibitor of MDMX suppresses cervical cancer cells via the inhibition of E6-E6AP-p53 axis

Dysfunction of p53 is observed in many malignant tumors, which is related to cancer susceptibility. In cervical cancer, p53 is primarily degradated through the complex of high-risk human papillomaviruses (HPV) oncoprotein E6 and E6-associated protein (E6AP) ubiquitin ligase. What is less clear is the mechanism and role of murine double minute X (MDMX) in cervical carcinogenesis due to the inactive status of murine double minute 2 (MDM2). In the current study, XI-011 (NSC146109), a small-molecule inhibitor of MDMX, showed robust anti-proliferation activity against several cervical cancer cell lines. XI-011 promoted apoptosis of cervical cancer cells via stabilizing p53 and activating its transcription activity. Moreover, XI-011 inhibited the growth of xenograft tumor in HeLa tumor-bearing mice, as well as enhanced the cytotoxic activity of cisplatin both in vitro and in vivo. Interestingly, MDMX co-localized with E6AP and seems to be a novel binding partner of E6AP to promote p53 ubiquitination. In conclusion, this work revealed a novel mechanism of ubiquitin-dependent p53 degredation via MDMX-E6AP axis in cervical carcinogenesis, and offered the first evidence that MDMX could be a viable drug target for the treatment of cervical cancer.

Multiple protease-activated probody-drug conjugates for treating CD147-positive ovarian cancer with limited toxicity

Traditional antibody-drug conjugates (ADCs) that target antigens expressed not only on tumor cells but also on nonmalignant cells are often associated with unavoidable on-target off-tumor toxicities. Probodies are masked antibody prodrugs that remain inactive until proteolytically activated in the tumor microenvironment (TME). However, most probodies are produced on the basis of a monoresponsive design and achieve a narrow therapeutic index owing to tumor heterogeneity and nonspecific payload-conjugation. Here, we generated different probodies targeting the cluster of differentiation 147 (CD147) antigen based on the design of multiple-protease-activated linker peptide and HcHAb18 antibody epitope-derived masking peptides. Three anti-CD147 probody-drug conjugates (PDCs) were produced via site-specific conjugation with cytotoxic monomethyl auristatin E (MMAE) through mild cysteine-selective chemical reactions. The created probodies and PDCs can be activated through cleavage by the proteases legumain, matrix-metalloproteinases 9, and urokinase-type plasminogen activator, but exhibit different CD147-targeting potentials. Importantly, PDC1, one of the conditional antibody architectures, exhibits highly selective targeting and strongest cytotoxicity to ovarian cancer cells. More importantly, PDC1 demonstrated promising targeting selectivity and improved the tumor-inhibition efficiency in ovarian cancer-xenograft mouse models without systemic toxicity. This multiple protease-activated, disulfide-bridging PDC strategy provides a novel, precise and safe ADC-targeted therapeutics against ovarian cancer.

Pro-inflammatory cytokines and CXC chemokines as game-changer in age-associated prostate cancer and ovarian cancer: Insights from preclinical and clinical studies' outcomes

Prostate cancer (PC) and Ovarian cancer (OC) are two of the most common types of cancer that affect the reproductive systems of older men and women. These cancers are associated with a poor quality of life among the aged population. Therefore, finding new and innovative ways to detect, treat, and prevent these cancers in older patients is essential. Finding biomarkers for these malignancies will increase the chance of early detection and effective treatment, subsequently improving the survival rate. Studies have shown that the prevalence and health of some illnesses are linked to an impaired immune system. However, the age-associated changes in the immune system during malignancies such as PC and OC are poorly understood. Recent research has suggested that the excessive production of inflammatory immune mediators, such as interleukin-6 (IL-6), interleukin-8 (IL-8), transforming growth factor (TGF), tumor necrosis factor (TNF), CXC motif chemokine ligand 1 (CXCL1), CXC motif chemokine ligand 12 (CXCL12), and CXC motif chemokine ligand 13 (CXCL13), etc., significantly impact the development of PC and OC in elderly patients. Our review focuses on the latest functional studies of pro-inflammatory cytokines (interleukins) and CXC chemokines, which serve as biomarkers in elderly patients with PC and OC. Thus, we aim to shed light on how these biomarkers affect the development of PC and OC in elderly patients. We also examine the current status and future perspective of cytokines (interleukins) and CXC chemokines-based therapeutic targets in OC and PC treatment for elderly patients.

Intratumor microbiome-derived butyrate enhances progesterone sensitivity by inducing ferroptosis in endometrial cancer

Endometrial cancer (EC) is increasingly affecting younger women, and progesterone therapy remains the cornerstone of fertility-preserving treatment (FPT). However, progesterone resistance presents a major clinical challenge. While the tumor microbiome and its metabolites have been implicated in various cancers, their role in EC and treatment resistance remains poorly understood. In this study, we comprehensively characterized the intratumor microbiota of 72 early-stage EC patients undergoing FPT using 16S rRNA sequencing. We found that patients who were sensitive to medroxyprogesterone acetate (MPA) had significantly higher alpha and beta diversity of intratumor microbiota compared to resistant patients. At the genus level, several butyrate-producing bacteria, including Butyrivibrio, Clostridium, and Faecalibacterium, were enriched in the MPA sensitive group. Targeted qPCR and metabolomic analyses confirmed the presence of these bacteria and elevated butyrate levels in tumor tissues. Functionally, butyrate suppressed tumor cell proliferation and enhanced MPA sensitivity both in vitro and in vivo. Mechanistically, butyrate promoted ferroptosis by downregulating CISD1. Butyrate-induced CISD1 inhibition enhanced iron accumulation, ROS generation, GPX4 expression, and HMGB1 release, thereby promoting ferroptosis. Overexpression of CISD1 partially rescued the ferroptosis of butyrate, confirming its role in mediating progesterone sensitivity. In addition, butyrate upregulated progesterone receptor expression, which further supported its role in sensitizing EC cells to progesterone therapy. This study is the first to demonstrate the critical role of the EC tumor microbiome and its metabolite butyrate in modulating progesterone response in FPT. Our findings provide a new mechanistic insight and offer a strong rationale for targeting the microbiota-ferroptosis axis to overcome progesterone resistance in EC patients.

Developing patient-derived organoids to demonstrate JX24120 inhibits SAMe synthesis in endometrial cancer by targeting MAT2B

Endometrial cancer (EC) is one of the most common gynecologic malignancies, which lacking effective drugs for intractable conditions or patients unsuitable for surgeries. Recently, the patient-derived organoids (PDOs) are found feasible for cancer research and drug discoveries. Here, we have successfully established a panel of PDOs from EC and conducted drug repurposing screening and mechanism analysis for cancer treatment. We confirmed that the regulatory β subunit of methionine adenosyltransferase (MAT2B) is highly correlated with malignant progression in endometrial cancer. Through drug screening on PDOs, we identify JX24120, chlorpromazine derivative, as a specific inhibitor for MAT2B, which directly binds to MAT2B (K

HPV E7-drived ALKBH5 promotes cervical cancer progression by modulating m6A modification of PAK5

Human papillomavirus (HPV) infection is a causative agent of cervical cancer (CC). N6-methyladenosine (m6A) modification is implicated in carcinogenesis and tumor progression. However, the involvement of m6A modification in HPV-involved CC remains unclear. Here we showed that HPV E6/7 oncoproteins affected the global m6A modification and E7 specifically promoted the expression of ALKBH5. We found that ALKBH5 was significantly upregulated in CC and might serve as a valuable prognostic marker. Forced expression of ALKBH5 enhanced the malignant phenotypes of CC cells. Mechanistically, we discovered that E7 increased ALKBH5 expression through E2F1-mediated activation of the H3K27Ac and H3K4Me3 histone modifications, as well as post-translational modification mediated by DDX3. ALKBH5-mediated m6A demethylation enhanced the expression of PAK5. The m6A reader YTHDF2 bound to PAK5 mRNA and regulated its stability in an m6A-dependent manner. Moreover, ALKBH5 promoted tumorigenesis and metastasis of CC by regulating PAK5. Overall, our findings herein demonstrate a significant role of ALKBH5 in CC progression in HPV-positive cells. Thus, we propose that ALKBH5 may serve as a prognostic biomarker and therapeutic target for CC patients.

MAP30 protein from Momordica charantia is therapeutic and has synergic activity with cisplatin against ovarian cancer in vivo by altering metabolism and inducing ferroptosis

Increasing evidence shows that Traditional Chinese Medicine (TCM) has an obvious appeal for cancer treatment, but there is still a lack of scientific investigation of its underlying molecular mechanisms. Bitter melon or bitter gourd (Momordica charantia) is an edible fruit that is commonly consumed, and it is used to cure different diseases in various ancient folk medical practices. We report that a bioactive protein, MAP30, isolated from bitter melon seeds exhibited potent anticancer and anti-chemoresistant effects on ovarian cancer cells. Functional studies revealed that MAP30 inhibited cancer cell migration, cell invasion, and cell proliferation in various ovarian cancer cells but not normal immortalized ovarian epithelial cells. When administered with cisplatin, MAP30 produced a synergistic effect on cisplatin-induced cell cytotoxicity in ovarian cancer cells. When low doses of cisplatin and MAP30 were co-injected intraperitoneally, a remarkable reduction of tumor dissemination and tumor growth was observed in an ovarian cancer ascites mouse model. Notably, blood tests confirmed that MAP30 did not cause any adverse effects on liver and kidney functions in the treated mice. MAP30 activated AMP-activated protein kinase (AMPK) signaling via CaMKKβ and induced cell cycle arrest in the S-phase. MAP30 modulated cell metabolism of ovarian cancer cells via suppression of GLUT-1/-3-mediated glucose uptake, adipogenesis, and lipid droplet formation in tumor development and progression. MAP30 also induced an increase in intracellular Ca

Natural and synthetic compounds in Ovarian Cancer: A focus on NRF2/KEAP1 pathway

Among gynecologic malignancies, ovarian cancer is one of the most dangerous, with a high fatality rate and relapse due to the occurrence of chemoresistance. Many researchers demonstrated that oxidative stress is involved in tumor occurrence, development and procession. Nuclear factor erythroid 2-related factor 2 (NRF2) is an important transcription factor playing an important role in protecting against oxidative damage. Increased levels of Reactive Oxygen Species (ROS) activate NRF2 signaling inducing the expression of antioxidant enzymes such as heme oxygenase (HO-1), catalase (CAT), glutathione peroxidase (GPx) and superoxide dismutase (SOD) that protect cells against oxidative stress. However, NRF2 activation in cancer cells is responsible for the development of chemoresistance inactivating drug-mediated oxidative stress that normally leads cancer cells to death. In this review we analyzed the current literature regarding the role of natural and synthetic compounds in modulating NRF2/KEAP1 (Kelch Like ECH Associated Protein 1) pathway in in vitro models of ovarian cancer. In particular, we reported how these compounds can modulate chemotherapy response.

Developing patient-derived organoids to predict PARP inhibitor response and explore resistance overcoming strategies in ovarian cancer

With the common use of poly ADP-ribose polymerase inhibitors (PARPi) for the man-agement of epithelial ovarian cancer (EOC) across the treatment life cycle, there is a critical need for the development of functional tests, as a complementary to genomic assays, in the study of PARPi sensitivity and resistance. Patient-derived organoids (PDOs) are found feasible for rapid functional testing and predicting drug response. Here, we established a series of PDOs from EOC and tested the sensitivity of seven cases to various agents including PARPi. PDOs recapitulated patient clinical response to platinum chemotherapy and displayed drug response heterogeneity to targeted agents including PARPi. Of three PDOs harboring mutational signature of homologous recombination repair (HRR) deficiency, two were PARPi sensitive while one was inherent resistant. Another PDO derived from a patient who relapsed during olaparib maintenance therapy was found acquired resistant to PARPi. Subsequent functional analysis revealed the potential resistant mechanisms related to replication fork protection and HRR functional restoration, and combination strategies targeting the mechanisms could reverse the resistance. Our research demonstrated the capacity of EOC PDOs for evaluating the sensitivity to PARPi under different settings, exploring mechanisms of resistance, and identifying effective combined strategies, which has implications for the clinical application of PARPi.

Cell cycle checkpoints and beyond: Exploiting the ATR/CHK1/WEE1 pathway for the treatment of PARP inhibitor–resistant cancer

Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) have become a mainstay of therapy in ovarian cancer and other malignancies, including BRCA-mutant breast, prostate, and pancreatic cancers. However, a growing number of patients develop resistance to PARPis, highlighting the need to further understand the mechanisms of PARPi resistance and develop effective treatment strategies. Targeting cell cycle checkpoint protein kinases, e.g., ATR, CHK1, and WEE1, which are upregulated in response to replication stress, represents one such therapeutic approach for PARPi-resistant cancers. Mechanistically, activated cell cycle checkpoints promote cell cycle arrest, replication fork stabilization, and DNA repair, demonstrating the interplay of DNA repair proteins with replication stress in the development of PARPi resistance. Inhibitors of these cell cycle checkpoints are under investigation in PARPi-resistant ovarian and other cancers. In this review, we discuss the cell cycle checkpoints and their roles beyond mere cell cycle regulation as part of the arsenal to overcome PARPi-resistant cancers. We also address the current status and recent advancements as well as limitations of cell cycle checkpoint inhibitors in clinical trials.