Bortezomib and etoposide combinations exert synergistic effects on the human prostate cancer cell line PC-3

Abstract

Abstract. Novel treatment modalities are urgently required for androgen-independent prostate cancer. In order to develop an alternative treatment for prostate cancer, the cytotoxic effects of the 26S proteasome inhibitor bortezomib, either alone or in combination with the two commonly used chemotherapeutic agents irinotecan and etoposide, on the human prostate cancer cell line PC-3 were evaluated in the present study. The PC-3 cell line was maintained in Dulbecco's modified Eagle's medium with 10% fetal bovine serum and treated with various doses of bortezomib, irinotecan, etoposide or their combinations. The growth inhibitory and cytotoxic effects were determined by water-soluble tetrazolium (WST)-1 assay, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay or iCELLigence system. The combination index values were determined by the Chou-Talalay method. The half maximal inhibitory concentration (IC 50 ) value of bortezomib on the PC-3 cell line was determined to be 53.4 nM by WST-1 assay, whereas the IC 50 values of irinotecan and etoposide were determined to be 2.1 and 26.5 µM, respectively. These results suggest that the 26S proteasome inhibitor bortezomib is more potent, compared with irinotecan and etoposide, in the androgen-insensitive and tumor protein p53-null cell line PC-3. The combined effects of bortezomib+irinotecan and bortezomib+etoposide were also tested on PC-3 cells. The effect of bortezomib+irinotecan combination was not significantly different than that produced by either monotherapy, according to the results of iCELLigence system and MTT assay. However, 40 nM bortezomib+5 µM etoposide or 40 nM bortezomib+20 µM etoposide combinations were observed to be more effective than each drug tested alone. The results of the current study suggest that bortezomib and etoposide combination may be additionally evaluated in clinical trials for the treatment of hormone-refractory prostate cancer.

Metuzumab enhanced chemosensitivity and apoptosis in non-small cell lung carcinoma

“…The effect of metuzumab, gemcitabine or the metuzumab/gemcitabine combination on cell viability were assessed by MTT assay as described previously. 39,40 Briefly, 5 × 10 3 NSCLC cells (A549, NCI-H460 and NCI-H520) were seeded in 96-well plate and cultured in 24 h, metuzumab, gemcitabine, the metuzumab/gemcitabine combination and saline were added to the cells. After additional 24h of respective treatments, 20 μL of MTT (5 mg/ml) was added into the wells and cells were incubated for 4 hours.…”

Identification of genes required for enzalutamide resistance in castration-resistant prostate cancer cellsin vitro

“…Our final gene, PSMD12, has not been previously implicated in prostate cancer, but dysregulation of the proteasome has been associated with prostate cancer. Inhibition of the proteasome with therapeutics like bortezomib has been shown to increase the efficacy of first generation anti-androgens like bicalutamide by decreasing the expression of AR and AR-V [41] or induce sensitivity of AR-independent prostate cancer cells to etoposide [42]. Unfortunately, proteasome inhibitors, to date, have proven acutely toxic, and targeting PSMD12 with currently available therapeutics is unlikely to provide a favorable risk-to-benefit ratio.…”

Effects of carfilzomib alone and in combination with cisplatin on the cell death in cisplatin-sensitive and cisplatin-resistant ovarian carcinoma cell lines

“…Large proteolytic complexes of proteasome are normally labeled with Ubiquitin which systematically destroys more than 80 % of regulatory proteins associated with regulation of cell cycle, cell death and differentiation by spontaneously increasing the accumulation of pro-apoptotic proteins and decreasing the activity and degradation of NF-kB (14,15). Studies have revealed that selective proteasome inhibitors induce cell death by making them susceptible to chemotherapeutic agents in the breast (16), prostate (17), pancreatic (18), and ovarian cancers (19). In 2012, Carfi lzomib (an epoxomycin derivative) has been approved by the Food and Drug Administration (FDA) as the second generation proteasome inhibitor for the treatment of multiple myeloma, showing lower toxicity than the classic proteasome inhibitors (20).…”