Sensitizing the cytotoxic action of Docetaxel induced by Pentoxifylline in a PC3 prostate cancer cell line

Abstract

Background Prostate cancer is one of the most frequently diagnosed types of cancers worldwide. In its initial period, the tumor is hormone-sensitive, but in advanced states, it evolves into a metastatic castration-resistant tumor. In this state, chemotherapy with taxanes such as Docetaxel (DTX) comprises the first line of treatment. However, the response is poor due to chemoresistance and toxicity. On the other hand, Pentoxifylline (PTX) is an unspecific inhibitor of phosphodiesterases; experimental, and clinically it has been described as sensitizing tumor cells to chemotherapy, increasing apoptosis and decreasing senescence. We study whether the PTX sensitizes prostate cancer cells to DTX for greater effectiveness. Methods PC3 human prostate cancer cells were treated in vitro at different doses and times with PTX, DTX, or their combination. Viability was determined by the WST-1 assay by spectrophotometry, cell cycle progression, apoptosis, generic caspase activation and senescence by flow cytometry, DNA fragmentation and caspases-3, -8, and -9 activity by ELISA. Results We found that PTX in PC3 human prostate cancer cells induces significant apoptosis per se and increases that generated by DTX, while at the same time it reduces the senescence caused by the chemotherapy and increases caspases-3,-8, and -9 activity in PTX + DTX-treated cells. Both treatments blocked the PC3 cell in the G1 phase. Conclusions Our results show that PTX sensitizes prostate tumor cells to apoptosis induced by DTX. Taken together, the results support the concept of chemotherapy with rational molecular bases.

Chemosensitizing effect of pentoxifylline in sensitive and multidrug-resistant non-small cell lung cancer cells

“…Our recent work discovered that pentoxifylline, an anti-fibrotic drug approved for the treatment of vascular diseases [ 15 , 16 ] , increased the response of pancreatic cancer cells to gemcitabine treatment [ 17 ] . The chemosensitizing effect of pentoxifylline has also been described in cervical [ 18 , 19 ] , prostate [ 20 ] , and human pancreatic tumor xenografts [ 21 ] . In NSCLC cells, Ohsaki et al reported the benefit of combining pentoxifylline with cisplatin and etoposide by interfering with the cell cycle [ 22 ] .…”

Molecular-based rational chemotherapy in cancer

“…In prostate cancer in vitro, inhibition of a kappa-lightchain-enhancer of activated B-cells (NF-kB) by pentoxifylline enhances docetaxel-induced apoptosis, and pentoxifylline alone has also been found to possess antitumor activity comparable to that of docetaxel 5 . The use of this hemorheology in clinical studies has yielded good results.…”