A selective retinoid X receptor agonist bexarotene (Targretin) prevents and overcomes acquired paclitaxel (Taxol) resistance in human non-small cell lung cancer.
OBJECTIVE
Paclitaxel is an important anticancer agent for the treatment of non-small cell lung cancer (NSCLC). However, its use in cancer therapy is limited by development of acquired drug resistance. The goal of this study was to determine the effect of bexarotene on development of acquired paclitaxel resistance in NSCLC.


METHODS
Human NSCLC Calu3 cells were repeatedly treated in culture with intermittent paclitaxel alone or in combination with continuous bexarotene for 3 months. Thereafter, cells were isolated and characterized for their drug sensitivity in vitro and in vivo.


RESULTS
Repeat exposure to paclitaxel alone resulted in development of paclitaxel resistance with cross-resistance to multidrug resistance P-glycoprotein substrates, whereas the bexarotene/paclitaxel combination prevented the development of drug resistance and the cells remained chemosensitive. Furthermore, paclitaxel resistance could be overcome when the resistant cells were treated with the combination regimen. Fluctuation analysis showed that treatment with bexarotene decreased the rate of spontaneous development of paclitaxel resistance. In vivo, the bexarotene/paclitaxel combination regimen produced a statistically significant decrease in tumor growth in a Calu3 NSCLC xenograft model compared with the single agents (two-tailed, P < 0.05). In addition, paclitaxel-resistant Calu3 tumors treated with the bexarotene/paclitaxel combination showed greater delay in tumor growth compared with those treated with paclitaxel alone.


CONCLUSIONS
Our results suggest that bexarotene may offer a novel approach to prevent and overcome paclitaxel resistance in patients with NSCLC.
Yen
Wan-Ching
WC
Department of Molecular Oncology, Ligand Pharmaceuticals, Inc., San Diego, California.
Corpuz
Manny R
MR
Prudente
Rene Y
RY
Cooke
Tracy A
TA
Bissonnette
Reid P
RP
Negro-Vilar
Andrés
A
Lamph
William W
WW
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000077610:Bexarotene; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control*; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D017239:Paclitaxel / Q000008:administration & dosage; D047488:Retinoid X Receptors / Q000819:agonists*; D015996:Survival Rate; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured / Q000637:transplantation
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D047488:Retinoid X Receptors; D013764:Tetrahydronaphthalenes; D000077610:Bexarotene; D017239:Paclitaxel