adarotene and Lung-Neoplasms

Adarotene belongs to the so-called class of atypical retinoids. The presence of the phenolic hydroxyl group on Adarotene structure allows a rapid O-glucuronidation as a major mechanism of elimination of the drug, favoring a fast excretion of its glucuronide metabolite in the urines. A series of ether, carbamate and ester derivatives was synthesized. All of them were studied and evaluated for their stability at different pH. The cytotoxic activity in vitro on NCI-H460 non-small cell lung carcinoma and A2780 ovarian tumor cell lines was also tested. A potential back-up of Adarotene has been selected to be evaluated in tumor models.

Topics: Animals; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Esterases; Humans; Lung Neoplasms; Mice; Mice, Nude; Retinoids; Transplantation, Heterologous

Growth and Differentiation Factor-15 (GDF-15, NAG-1, MIC-1) is induced by several apoptosis-inducing agents including the retinoid-related molecule (RRM) 6-[3-(1-adamantyl-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437). It has been suggested that GDF-15 may be involved in the induction of apoptosis by CD437 in H460 lung cancer cells. The present study was designed to probe this hypothesis more directly. Several RRMs (CD437, ST1926 and MX3350-1) but not the retinoids all-trans- retinoic acid and 4HPR were able to induce GDF-15 in H460 cells. A similar differential effect of these retinoids was observed for the induction of p53, which has been reported to regulate GDF-15 expression. In H460 cells transfected with a neo vector control (H460-Neo), treatment with RRMs but not ATRA or 4HPR resulted in increases in p53, GDF-15 and apoptosis evidenced by poly(ADP ribose) polymerase (PARP) cleavage. In contrast, RRMs failed to increase p53 or induce apoptosis in H460 cells in which p53 was inactivated by transfection of the human papillomavirus E6-6 (H460-E6-6). The increase in GDF-15 by RRMs was also compromised in the H460-E6-6 cells. Because PARP cleavage was only evident when GDF-15 levels where elevated it appeared that GDF-15 was mediating the pro-apoptotic effects of RRMs. However, silencing of GDF-15 induction by RNA interference failed to decrease the ability of CD437 and ST1926 to induce apoptosis. These results demonstrate that GDF-15 is dispensable for the pro-apoptotic activity of CD437 and ST1926.

Topics: Adamantane; Antineoplastic Agents; Apoptosis; Blotting, Western; Carcinoma, Large Cell; Cinnamates; Cytokines; Gene Expression Regulation, Neoplastic; Growth Differentiation Factor 15; Humans; Lung Neoplasms; Oncogene Proteins, Viral; Poly(ADP-ribose) Polymerases; Repressor Proteins; Retinoids; RNA, Small Interfering; Tretinoin; Tumor Cells, Cultured; Tumor Suppressor Protein p53