Journal of Chemotherapy

Aberrant epigenetic regulation of FZD3 by TET2 is involved in ovarian cancer cell resistance to cisplatin

A major challenge in platinum-based cancer therapy, including cisplatin (DDP), is the clinical management of chemo-resistant tumours, which have unknown pathogenesis at the level of epigenetic mechanism. To identify potential resistance mechanisms, we integrated ovarian cancers (OC)-related GEO database retrieval and prognostic analyses. The results of bioinformatics prediction showed that frizzled class receptor 3 (FZD3) was a DDP-associated gene and closely related to the prognosis of OC. DDP resistance in OC inhibited FZD3 expression. FZD3 reduced DDP resistance in OC cells, increased the inhibitory effect of DDP on the growth and aggressiveness of DDP-resistant cells, and promoted apoptosis and DNA damage. TET2 was reduced in OC. TET2 promoted the transcription of FZD3 through DNA hydroxymethylation. TET2 sensitized the drug-resistant cells to DDP

The effect of PARP inhibitors in homologous recombination proficient ovarian cancer: meta-analysis

BRCA1/2 mutations and homologous recombination deficiency (HRD) predispose to increased sensitivity to poly(ADP-ribose)polymerase (PARP) inhibitor treatment. Our aim was to evaluate the PARP inhibitors effect on progression free survival (PFS) in a subpopulation with homologous recombination proficient status (HRD-BRCA-). A systematic literature search was performed for all studies reporting on the effect of PARP inhibitors regarding PFS in the HRD-BRCA- subpopulation, in patients with epithelial ovarian, tubal or primary peritoneal cancers (EOC). Five studies were included, enrolling a population of 3413 patients, with 1070 of them being HRD-BRCA-. PARP inhibitors were effective in the treatment of EOC, regardless of HRD and BRCA status or line of therapy. The estimated pooled effect hazard ratio (HR), assessing PFS for PARP inhibitors compared with control, was 0.76 (95% CI: 0.65-0.88,

Predictors of olaparib discontinuation owing to adverse drug events in patients with ovarian, peritoneal, or fallopian tube cancer: a retrospective observational study

We investigated predictors of olaparib discontinuation owing to adverse effects. Patients with ovarian, peritoneal, or fallopian tube cancers treated with olaparib at Osaka Medical and Pharmaceutical University Hospital between April 2018 and September 2022 were included in this study. The exclusion criteria were as follows: discontinuation of treatment due to disease progression, use of anaemia medications, and use of cytochrome P450 (CYP3A4) inhibitors. The follow-up period was 90 d. Of the 46 eligible patients, 21 patients discontinued olaparib, including 15 patients with grade 3 or higher anaemia, eight patients with grade 3 or higher neutropenia, and four patients with non-haematological toxicity (including multiple onset). Multivariate logistic regression analysis showed that grade 4 neutropenia and anaemia progression to grades 2-3 due to chemotherapy administered before olaparib administration were predictors of olaparib discontinuation. The severity of neutropenia and anaemia due to chemotherapy before olaparib administration may be a potential marker for its discontinuation.

LncRNA-FGD5-AS1 promotes 5-Fu resistance of cervical cancer cells through modulating the miR-130a-3p-YTHDF2 axis

Cervical cancer is one of the most common gynecologic malignancies worldwide. 5-Fluorouracil (5-Fu) is a widely used anticancer drug for various cancers, but the development of 5-Fu resistance poses a challenge in treating cervical cancer patients. This study examined the roles and molecular mechanisms of LncRNA-FGD5-AS1 in 5-Fu resistant cervical cancer cells through in vitro and in vivo experiments. We discovered FGD5-AS1 and the RNA methylation reader protein, YTHDF2, were positively associated with 5-Fu resistance in cervical cancer. A positive correlation between FGD5-AS1 and YTHDF2 was found in cervical tumor tissues. Expressions of FGD5-AS1 and YTHDF2 were significantly upregulated in the established 5-Fu resistant cervical cancer cells. MiRNA-microArray analysis screened that FGD5-AS1 downregulated miR-130a-3p expression in cervical cancer cells. Subsequently, we demonstrated FGD5-AS1 acted as a ceRNA by sponging miR-130a-3p, which targeted the 3'UTR of YTHDF2 mRNA. Rescue experiments validated overexpression of FGD5-AS1 increased 5-Fu resistance in cervical cancer cells, which was reversed by miR-130a-3p overexpression. Finally, combining FGD5-AS1 silencing with 5-Fu treatments resulted in a synergistic inhibitory effect (CI < 1) on the viability of cervical cancer cells. This study reveals a FGD5-AS1-miR-130a-3p-YTHDF2 axis that could be a promising therapeutic target for overcoming 5-Fu resistance in cervical cancer.

Circ_0007841 knockdown confers cisplatin sensitivity to ovarian cancer cells by down-regulation of NFIB expression in a miR-532-5p-dependent manner

Cisplatin (DDP) is first-line management for ovarian cancer (OC). Previous data have suggested that circular RNA_0007841 (circ_0007841) regulates OC progression; however, there is no data on its role in the sensitivity of OC cells to DDP. RNA expression of circ_0007841, microRNA-532-5p (miR-532-5p) and nuclear factor I B (NFIB) was detected by quantitative real-time polymerase chain reaction in OC patient samples and OC cell lines. Protein expression was checked by Western blotting analysis. Cell viability, proliferation, cell apoptotic rate, migration and invasion were investigated by 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-diphenytetrazoliumromide, 5-Ethynyl-29-deoxyuridine, flow cytometry analysis, scratch test and transwell assays, respectively. The interactions among circ_0007841, miR-532-5p and NFIB were identified by a dual-luciferase reporter assay. Xenograft mouse model assay was performed to determine the effect of circ_0007841 on DDP sensitivity in vivo. Circ_0007841 and NFIB expression were upregulated, whereas miR-532-5p was downregulated in DDP-resistant OC tissues and cells compared with controls. Circ_0007841 silencing improved DDP sensitivity, inhibited cell proliferation, invasion and migration, but induced cell apoptosis in DDP-resistant OC cells. Circ_0007841 acted as a miR-532-5p sponge and regulated DDP resistance and OC cell malignancy through miR-532-5p in DDP-resistant OC cells. Besides, the overexpression of NFIB, a target of miR-532-5p, remitted miR-532-5p-mediated effects in DDP-resistant OC cells. Circ_0007841 depletion conferred DDP sensitivity to DDP-resistant OC cells in vivo. Further, circ_0007841 was secreted from DDP-resistant OC cells through being packaged into exosomes. Circ_0007841 conferred DDP resistance to DDP-resistant OC cells through the miR-532-5p/NFIB axis, suggesting the potential of circ_0007841 as a therapeutic target for OC.

Successful treatment with oxaliplatin and programmed cell death protein 1 inhibitor in recurrent advanced endometrial carcinoma with mismatch repair defects: a case report and literature review

The incidence of endometrial cancer (EC), a widely prevalent gynecological malignancy, is witnessing a global surge. Although early-stage cancer demonstrates promising outcomes, advanced cancer is associated with an unfavorable prognosis. Nevertheless, for specific pathological types or molecular subtypes of advanced EC, an accurate treatment algorithm can lead to a favorable prognosis. Here, we report a case of stage IVB EC characterized by mucinous differentiation with mismatch repair deficiencies (MMRd) who was successfully treated with combination of oxaliplatin and programmed cell death protein 1 (PD-1) inhibitor. Our findings emphasize the importance of conducting pathological and molecular typing assessments in individuals with advanced stage or recurrent EC. Additionally, combining oxaliplatin and PD-1 inhibitors may be a viable treatment option for EC with mucinous differentiation and MMRd. More representative and standardized studies are needed to consolidate this conclusion.

Rs3802278 in 3’-UTR of SULF1 associated with platinum resistance and survival in Chinese epithelial ovarian cancer patients

Ovarian cancer is the leading cause of death from gynecologic cancers, but platinum resistance remains a major obstacle in the chemotherapy of ovarian cancer. This study aims to examine the role of polymorphisms in sulfatase 1 (