The platinum (Pt)-containing antitumor drugs including cisplatin (cis-diamminedichloroplatinum II, cDDP), carboplatin, and oxaliplatin, have been the mainstay of cancer chemotherapy. These drugs are effective in treating many human malignancies. The major cell-killing target of Pt drugs is DNA. Recent findings underscored the important roles of Pt drug transport system in cancer therapy. While many mechanisms have been proposed for Pt-drug transport, the high-affinity copper transporter (hCtr1), Cu chaperone (Atox1), and Cu exporters (ATP7A and ATP7B) are also involved in cDDP transport, highlighting Cu homeostasis regulation in Pt-based cancer therapy. It was demonstrated that by reducing cellular Cu bioavailable levels by Cu chelators, hCtr1 is transcriptionally upregulated by transcription factor Sp1, which binds the promoters of Sp1 and hCtr1. In contrast, elevated Cu poisons Sp1, resulting in suppression of hCtr1 and Sp1, constituting the Cu-Sp1-hCtr1 mutually regulatory loop. Clinical investigations using copper chelator (trientine) in carboplatin treatment have been conducted for overcoming Pt drug resistance due in part to defective transport. While results are encouraging, future development may include targeting multiple steps in Cu transport system for improving the efficacies of Pt-based cancer chemotherapy. The focus of this review is to delineate the mechanistic interrelationships between Cu homeostasis regulation and antitumor efficacy of Pt drugs.

High collagen type XI alpha 1 (COL11A1) levels are associated with tumor progression, chemoresistance, and poor patient survival in several cancer types. MicroRNAs (miRNAs) are dysregulated in multiple cancers, including epithelial ovarian carcinoma (EOC); however, the regulation of COL11A1 by miRNAs in EOC remains unclear. We examined the role of miRNAs in regulating COL11A1 expression. We identified miR-509 and miR-335 as the candidate miRNAs through an online database search. EOC cell treatment with miR-335 mimics abrogated COL11A1 expression and suppressed cell proliferation and invasion, besides increasing the sensitivity of EOC cells to cisplatin. Conversely, treatment with miR-335 inhibitors prompted cell growth/invasiveness and chemoresistance of EOC cells. miR-335 inhibited COL11A1 transcription, thus reducing the invasiveness and chemoresistance of EOC cells via the Ets-1/MMP3 and Akt/c/EBPβ/PDK1 axes, respectively. Furthermore, it did not directly regulate PDK1 but increased PDK1 ubiquitination and degradation through COL11A1 inhibition. In vivo findings highlighted significantly decreased miR-335 mRNA expressions in EOC samples. Furthermore, patients with low miR335 levels were susceptible to advanced-stage cancer, poor response to chemotherapy, and early relapse. This study highlighted the importance of miR-335 in downregulating COL11A1-mediated ovarian tumor progression, chemoresistance, and poor survival and suggested its potential application as a therapeutic target.

Tissue inhibitor of metalloproteinases-3 (TIMP3) is vital in regulating several biological processes. TIMP3 exerts antitumour effects via matrix metalloproteinase (MMP)-dependent and MMP-independent pathways. Due to promoter methylation and miRNA binding, TIMP3 expression has been observed to decrease in various cancers. Consequently, the migration and invasion of cancer cells increases. Conflicting results have reported that expression levels of TIMP3 in primary and advanced cancers are higher than those in healthy tissues. Therefore, the role of TIMP3 in cancer biology and progression needs to be elucidated. This review provides an overview of TIMP3, from its biological function to its effects on various cancers. Moreover, gynaecological cancers are discussed in detail. TIMP3 has been associated with cervical adenocarcinoma as well as cancer development in serous ovarian cancer and breast cancer metastasis. However, the relationship between TIMP3 and endometrial cancers remains unclear. TIMP3 may be a useful biomarker for gynaecological cancers and is a potential target for future cancer therapy.

Advances in cervical cancer management for childbearing women have led to less radical approaches. Use of fertility-sparing treatment to treat small cell neuroendocrine carcinoma (SCNEC) is challenging owing to the aggressive nature of the disease, even in early stage disease. A 25-year-old nulligravida woman presented with malodorous vaginal discharge and was diagnosed to have an exophytic cervical SCNEC. A magnetic resonance image scan showed no evidence of parametrial invasion or distant metastasis. Clinical staging allocated her to stage IB1 disease. She underwent radical abdominal trachelectomy for reproductive purpose. Preoperative and postoperative chemotherapy with ifosfamide/etoposide/cisplatin combining gonadotropin-releasing hormone agonist were administered. She had a spontaneous, uneventful pregnancy and successfully delivered a term baby via cesarean section 7 years after treatment. To our knowledge, we describe the first success in offering a fertility-preserving multimodality strategy to present favorable oncologic, reproductive, and obstetric outcomes in a fertile woman of stage I SCNEC. Individualized multimodality therapy may be utilized in specific patients with early-stage cervical cancer to preserve their fertility.

This study aimed to determine the real-world, long-term prognostic impacts, and adverse effects (AEs) of bevacizumab (BEV) in Asian patients with ovarian/tubal/peritoneal cancers. We retrospectively reviewed the medical records of consecutive patients with ovarian/tubal/peritoneal cancer on front-line chemotherapy with or without BEV (Cohort 1) and those who relapsed following chemotherapy and/or BEV (Cohort 2) between 2011 and 2018 in a tertiary medical centre. Patient characteristics, BEV dosages, clinical outcomes, and AEs were analyzed. Hazard ratios for disease progression and death were analyzed using a cox proportional regression model. Benefits of BEV used throughout triweekly, in terms of improved progression-free survival (PFS) and overall survival (OS), were observed at a dosage of 7.5–15 mg/kg among advanced-stage Cohort 1 patients. A progression-free interval of <6 months was the strongest predictor of disease progression and death in advanced-stage patients. BEV throughout and optimal cytoreduction were independent predictors of reduced disease progression. No prognostic advantage was observed between serous and clear cell histologies when BEV was added. Moreover, BEV resulted in improved OS in Cohort 2 patients, especially in the platinum-sensitive subgroup. Most patients had a front-line BEV dosage <10 mg/kg per cycle with <10 treatment cycles. Low rates and grades of BEV-related AEs were observed in both cohorts. BEV used throughout effectively extended PFS and OS in advanced-stage patients with ovarian/tubal/peritoneal cancer. Patients with platinum-sensitive carcinoma, treated with BEV, had a significant improvement in OS and extended PFS. Therefore, BEV can safely be added to chemotherapy for ovarian/tubal/peritoneal cancers.