Combined effect of navelbine with medroxyprogesterone acetate against human breast carcinoma MCF-7 cells in vitro

Abstract

Summary Navelbine (NVB, vinorelbine ditartrate, KW-2307), a new vinca alkaloid analogue, has been shown to be clinically effective against advanced breast cancer. In this report, the combined effect of NVB with medroxyprogesterone acetate (MPA), a synthetic progesterone derivative, was examined in vitro against human breast carcinoma MCF-7 cells. The combined effect was demonstrated to be synergistic using the isobologram and median-effect plot analyses. To elucidate the mechanism of action, we further examined effects of both drugs on cell cycle distribution of the cells in combination and/or alone. NVB at 2 nm induced apparent G1-phase accumulation as well as the induction of cyclin-dependent kinase (CDK) inhibitor p21WAF1/cIPl protein and the dephosphorylated form of retinoblastoma protein (pRb). In contrast, MPA at 0.1 gM also induced G1-phase accumulation as well as the reduced expression of cyclin Dl protein. In addition, the combination of both drugs induced augmented G1-phase accumulation, which occurred along with p21WAF1/cIPl protein induction, cyclin Dl protein reduction and pRb dephosphorylation. These results demonstrate that the synergistic combined effect of NVB with MPA was mediated through enhancement of G1-phase accumulation that resulted from the different action point(s) of each drug. Furthermore, the synergistic combined effect of NVB with MPA was also observed in other human breast carcinoma cell lines, such as T-47D and ZR-75-1. These results suggest that combination therapy of NVB with MPA in breast cancer might be effective in clinical studies.

Metronomic vinorelbine is directly active on Non Small Cell Lung Cancer cells and sensitizes the EGFRL858R/T790M cells to reversible EGFR tyrosine kinase inhibitors

“…In addition, our attention focused on another important mechanism that was previously associated with this vinca alkaloid compound at higher concentrations. Both Sugiyama et al [43] and Roncuzzi et al [44] described a significant downregulation of cyclin-D1 after exposure to standard concentrations of VNR. Similarly, mVNR on NSCLC cells significantly reduced both cyclin-D1 gene expression and protein levels after 144 h of exposure in treated NSCLC cells if compared to controls.…”

Oral metronomic vinorelbine combined with endocrine therapy in hormone receptor-positive HER2-negative breast cancer: SOLTI-1501 VENTANA window of opportunity trial

“…Prior studies have evaluated and studied the combination of vinorelbine and endocrine therapy. In the preclinical setting, synergistic activity between vinorelbine and hormone therapy has been observed [16]. In the clinical setting, a single-arm phase II clinical trial combining vinorelbine and tamoxifen in 38 evaluable patients as the first-line therapy, of whom 63% had positive and 29% unknown hormonal receptor status, the overall response rate was 66% and the complete response rate was 16%.…”

“…In common with other agents in this class, vinorelbine (25–30 mg/m 2 iv on days 1 and 8 every 3 weeks) blocks cells at G2/M when present at concentrations close to the IC50 [14]. In a Luminal/HER2-negative breast cancer model (i.e., MCF7), vinorelbine at 2 nM induced apparent G1-phase accumulation as well as the induction of CDK inhibitor p21(WAF1/CIP1) protein and the dephosphorylated form of retinoblastoma protein [16]. In breast cancer, a wide range of phase II and III studies have now established the activity of vinorelbine alone, or in combination with other chemotherapeutic agents, in the treatment of early and advanced breast cancer [17].…”

Cytotoxic activity and molecular modeling of progestins - pregna-D'-pentarans

“…Все исследованные соединения, за исключением прогестерона I, оказывают действие на рост MCF-7, сопоставимое с действием другого представителя класса прогестинов -медроксипрогестерон ацетата (IC 50~1 0 мкМ) [20]. Наибольший цитотоксический эффект выявлен при инкубации клеток MCF-7 с соединениями IV и V.…”