Differential responses of normal, premalignant, and malignant human bronchial epithelial cells to receptor-selective retinoids.
Using an in vitro lung carcinogenesis model consisting of normal, premalignant, and malignant human bronchial epithelial (HBE) cells, we analyzed the growth inhibitory effects of 26 novel synthetic retinoic acid receptor (RAR)- and retinoid X receptor (RXR)-selective retinoids. RAR-selective retinoids such as CD271, CD437, CD2325, and SR11364 showed potent activity in inhibiting the growth of either normal or premalignant and malignant HBE cells (IC50s mostly <1 microM) and were much more potent than RXR-selective retinoids. Nonetheless, the combination of RAR- and RXR-selective retinoids exhibited additive effects in HBE cells. As the HBE cells became progressively more malignant, they exhibited decreased or lost sensitivity to many retinoids. The activity of the RAR-selective retinoids, with the exception of the most potent retinoid, CD437, could be suppressed by an RAR panantagonist. These results suggest that: (a) RAR/RXR heterodimers play an important role in mediating the growth inhibitory effects of most retinoids in HBE cells; (b) CD437 may act through an RAR-independent pathway; (c) some of the RAR-selective retinoids may have the potential to be used in the clinic as chemopreventive and chemotherapeutic agents for lung cancer; and (d) early stages of lung carcinogenesis may be responsive targets for chemoprevention by retinoids, as opposed to later stages.
Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston 77030, USA. ssun@notes.mdacc.tmc.edu
S Y
SY
Sun
J M
JM
Kurie
P
P
Yue
M I
MI
Dawson
B
B
Shroot
R A
RA
Chandraratna
W K
WK
Hong
R
R
Lotan
D000970:Antineoplastic Agents / Q000494:pharmacology; D001980:Bronchi / Q000187:drug effects*; D001984:Bronchial Neoplasms / Q000188:drug therapy / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D018890:Chemoprevention; D019008:Drug Resistance, Neoplasm; D004847:Epithelial Cells / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D011230:Precancerous Conditions; D018168:Receptors, Retinoic Acid / Q000819:agonists / Q000037:antagonists & inhibitors*; D012176:Retinoids / Q000138:chemical synthesis / Q000494:pharmacology*; D014212:Tretinoin / Q000494:pharmacology
D000970:Antineoplastic Agents; D018168:Receptors, Retinoic Acid; D012176:Retinoids; D014212:Tretinoin