作者: Perez-Rodriguez, Santiago ; Ortiz, Maria A. ; Pereira, Raquel ; Rodriguez-Barrios, Fatima ; de Lera, Angel R. ; Piedrafita, F. Javier
Retinoid-related molecules with an adamantyl group (adamantyl arotinoids) have been described with selective activities towards the retinoid receptors as agonists for NR1B2 and NR1B3 (RARbeta,gamma) (CD437, MX3350-1) or RAR antagonists (MX781) that induce growth arrest and apoptosis in cancer cells. Since these molecules induce apoptosis independently of RAR transactivation, we set up to synthesize novel analogs with impaired RAR binding. Here we describe adamantyl arotinoids with 2,2'-disubstituted biaryl rings prepared using the Suzuki coupling of the corresponding fragments. Those with cinnamic and naphthoic acid end groups showed significant antiproliferative activity in several cancer cell lines, and this effect correlated with the induction of apoptosis as measured by caspase activity. Strikingly, some of these compounds, whereas devoid of RAR binding capacity, were able to activate RXR.
2006-10-01·Cell Death and Differentiation1区 · 生物学
Higher potency of the synthetic retinoid MX3350-1 compared to the natural all-trans-retinoic acid in modulation of cell cycle and induction of apoptosis in head and neck squamous carcinoma cells
1区 · 生物学
作者: Chun, K.-H. ; Lotan, R.
Retinoids, vitamin A analogs, have been shown to suppress carcinogenesis in exptl. animals and exhibit chemopreventive and therapeutic effects in clin. trials including chemoprevention of head and neck squamous cell carcinoma (HNSCC). At least some of these effects could be related to the finding that all-trans-retinoic acid (ATRA) inhibited the growth and suppressed aberrant squamous differentiation in different HNSCC cell lines. New synthetic retinoic acid analogs were prepared and screened for improved activity. One of these retinoids, MX3350-1, was a potent inhibitor of cell growth and strong inducer of apoptosis. MX3350-1 may be useful for treatment of ATRA-resistant HNSCC and possibly other cancers.
2005-05-19·Oncogene1区 · 医学
Induction of apoptosis by the synthetic retinoid MX3350-1 through extrinsic and intrinsic pathways in head and neck squamous carcinoma cells
1区 · 医学
作者: Chun, Kyung-Hee ; Pfahl, Magnus ; Lotan, Reuben
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.