Induction of apoptosis by the synthetic retinoid MX3350-1 through extrinsic and intrinsic pathways in head and neck squamous carcinoma cells.
Retinoids have shown promise in cancer prevention and therapy. As some retinoids exhibit undesirable side effects, new retinoid analogs have been synthesized. In this study, we examined the effects of the retinoid MX3350-1 on human head and neck squamous cell carcinoma (HNSCC) cell lines. MX3350-1 suppressed the growth of 7/8 HNSCC cell lines by >65%. This inhibition appeared to be due to induction of apoptosis as revealed by the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay. Studies with cell line UMSCC17B indicated that apoptosis was induced within 1-2 days and involved activation of caspase-8, -9, and -3. Inhibitors of these caspases suppressed MX3350-1-induced apoptosis. MX3350-1 decreased the levels of antiapoptotic Bcl-2 and Bcl-XL, increased proapoptotic Bax, induced mitochondrial membrane permeabilization (MMP), and cytochrome c release from mitochondria to cytosol. The antioxidant butylated hydroxyanisol and the MMP inhibitor cyclosporin A (Cs A) blocked apoptosis induced by MX3350-1. In contrast, retinoid receptor antagonists failed to inhibit apoptosis. MX3350-1 increased the levels of Fas-ligand, Fas, and Fas-associated death domain, and enhanced activation of procaspase-8 and cleavage of its substrate Bid. Soluble Fas rescued the cells from MX3350-1-induced apoptosis. These results demonstrate that MX3350-1 induces apoptosis by activating both extrinsic and intrinsic apoptosis pathways and suggest that further studies on the potential of this retinoid for prevention and therapy of HNSCCs are warranted.
Chun
Kyung-Hee
KH
Department of The University of Texas MD Anderson Cancer Center, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Pfahl
Magnus
M
Lotan
Reuben
R
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000473:pathology*; D020169:Caspases / Q000187:drug effects; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006258:Head and Neck Neoplasms / Q000473:pathology*; D006801:Humans; D020287:In Situ Nick-End Labeling; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors; D047488:Retinoid X Receptors / Q000037:antagonists & inhibitors; D012176:Retinoids / Q000494:pharmacology*; D015398:Signal Transduction
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D012176:Retinoids; D020169:Caspases