Docetaxel-ST1481 sequence exerts a potent cytotoxic activity on hormone-resistant prostate cancer cells by reducing drug resistance-related gene expression.
BACKGROUND
The efficacy of current therapy for hormone-refractory prostate cancer is still unsatisfactory and new agents and therapeutic modalities are needed. The aims of the present work were to examine the in vitro activity and mechanisms of action of different antitumor drug combinations in hormone-resistant prostate cancer (HRPC) cell lines.


METHODS
The activity of docetaxel (Doc), cisplatin (Cis), oxaliplatin (Oxa), SN-38 and ST1481, singly or in combination, was assessed in different HRPC cell lines (PC3, parental DU145 and taxane-resistant DU145-R) by SRB test. Apoptosis was evaluated by TUNEL and ANN-V assays. Extrusion pump activity was studied by Hoechst 33342 assay, while gene expression related to drug efflux mechanisms and DNA damage repair was analyzed by RT-PCR.


RESULTS
Doc induced a high cytocidal effect in the HRPC cells, whereas Cis, Oxa, SN-38 and ST1481 exerted prevalently cytostatic activity. Doc followed by ST1481 proved to be the most effective drug sequence among those investigated, producing an important synergistic effect (R.I. from 2.0 to 5.2) in all the tested cell lines. Moreover, this sequence induced a significant downregulation of xenobiotic extrusion pump and DNA damage repair gene expression. ST1481 synergistically increased the cytocidal effect of Doc, probably through a downregulation of extrusion pump activity and DNA damage repair-related genes.


CONCLUSIONS
Our results show that the Doc --> ST1481 sequence effectively reduces the cancer cell population and restores Doc activity in taxane-resistant HRPC, indicating its potential usefulness as first- or second-line treatment of hormone-refractory prostate cancer.
Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), Meldola, Italy.
Francesco
F
Fabbri
Giovanni
G
Brigliadori
Silvia
S
Carloni
Paola
P
Ulivi
Anna
A
Tesei
Rosella
R
Silvestrini
Dino
D
Amadori
Wainer
W
Zoli
D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D000077146:Irinotecan; D008297:Male; D009944:Organoplatinum Compounds / Q000494:pharmacology; D000077150:Oxaliplatin; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D043823:Taxoids / Q000008:administration & dosage / Q000494:pharmacology*
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; C433984:ST 1481; D043823:Taxoids; D000077150:Oxaliplatin; D000077143:Docetaxel; D000077146:Irinotecan; D002945:Cisplatin; D002166:Camptothecin