A selective retinoid X receptor agonist bexarotene (LGD1069, Targretin) prevents and overcomes multidrug resistance in advanced prostate cancer.
BACKGROUND
We previously reported that a retinoid X receptor agonist bexarotene prevented and overcame acquired drug resistance in advanced breast cancer and non-small cell lung cancer. The present study was to evaluate the effect of bexarotene on the development of multidrug resistance in advanced prostate cancer.


METHODS
Human prostate cancer cells PC3 were repeatedly treated in culture with paclitaxel, doxorubicin, or cisplatin with or without bexarotene for 3 months. Thereafter, cells were isolated and characterized for their drug sensitivity.


RESULTS
Compared to parental cells, cells treated with a single therapeutic agent was resistant to the therapeutic agent, whereas cells treated with the combination remained chemosensitive. Cells with acquired drug resistance showed increased sensitivity to the cytotoxic agent when treated with the combination. Fluctuation analysis demonstrated that treatment with bexarotene decreased the rate of spontaneous development of drug resistance. These in vitro findings were further confirmed in the PC3 xenograft model.


CONCLUSIONS
Our results suggest a role of bexarotene in combination with chemotherapeutic agents in prevention and overcoming acquired drug resistance in advanced prostate cancer.
Yen
Wan-Ching
WC
Department of Molecular Oncology, Ligand Pharmaceuticals, Inc., San Diego, California 92121, USA. wyen@ligand.com
Lamph
William W
WW
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D000077610:Bexarotene; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D008819:Mice, Nude; D017239:Paclitaxel / Q000008:administration & dosage; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics; D012334:RNA, Neoplasm / Q000737:chemistry / Q000235:genetics; D047488:Retinoid X Receptors / Q000819:agonists*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D012334:RNA, Neoplasm; D047488:Retinoid X Receptors; D013764:Tetrahydronaphthalenes; D004317:Doxorubicin; D000077610:Bexarotene; D017239:Paclitaxel; D002945:Cisplatin