Abstract
Abstract
The molecular complexity of cancers and therapy-related side effects often limit efficacy of numerous anti-tumor therapies, and warrant development of new drugs that are specific for certain molecular targets while minimizing the off-target effects. We previously have synthesized a series of benzene-sulfonamides incorporating cyanoacrylamide moieties (tyrphostine analogues), and investigated such new compounds as inhibitors of the metalloenzyme carbonic anhydrase (CA). Specifically, we determined the inhibitory activity of such novel compounds against the cytosolic, house-keeping human (h) isoforms hCA I and II, as well as the transmembrane, tumor-associated ones CA IX and XII. Four compounds, namely CS2, CS6, CS8 and CS13, were very potent CA IX/XII inhibitors whereas they were much less effective as inhibitors of CA I and II. To determine whether these selective tumor-associated CA inhibitors exert antitumor activity, we examined their antiproliferative activity against the human medulloblastoma Daoy cell line, human hepatoma HepG2 cell line and the human epithelial cervical cancer Hela cell line. Compounds CS6 and CS13 showed significant antiproliferative activity against the three cancer cell lines. Daoy was the most sensitive cell line, and compound CS6 was the most potent one. Remarkably, compound CS6 was more potent against Daoy cells than the multi-targeted kinase inhibitor of BCR-ABL and SRC family kinases, dasatinib, since the former exerted smaller IC50 than that exerted by the latter (4.14 versus 7.28 μg/mL). In addition, flow cytometric Annexin-V/propidium iodide assay results showed that cell death induced by compounds CS6 is mediated, at least in part, by apoptosis. Moreover, CS6 significantly inhibited tyrosine kinase activity in Daoy cells, compared to DMSO-treated (control) cells. Taken together, these data indicate that compound CS6 is a novel multiple cancer pathways inhibitor, and warrants further investigation of its antitumor activity in medulloblastoma and other brain tumors. Currently, compounds CS6 and CS13 are being tested for their inhibitory activity against dihydrofolate reductase and thymidylate synthase.
Citation Format: Ahmed Mahmoud Alafeefy, Sabry Atia, Sheikh Ahmad, Khairy Zoheir, Abdelkader Ashour, Ashok Kumar. Development of novel selective tumor-associated carbonic anhydrase inhibitors as promising anticancer agents. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-100. doi:10.1158/1538-7445.AM2015-LB-100