Abstract B34: Pyrimidobenzimidazoles as a potential new drug to treat human melanoma

Melanoma is the most aggressive skin tumor due to its high capacity to metastasize and resistance to therapy, leading to poor prognosis and high mortality rates. Thus, the aim of this study was to investigate a possible antitumoral action of pyrimidobenzimidazole compounds in human melanoma lineages, SK-Mel-103, SK-Mel-28, and SK-Mel-28 resistant to vemurafenib. Using acute treatment (72 hours) it was possible to select two, among the seven compounds tested, by their effectiveness in decrease the cell viability, by MTT assay, in low concentrations. Further, using chronic assay (120 hours) it was possible to find the IC50 of the best compounds, PBZs 1 and 4. For cell line SK-Mel-103 the IC50 value was 3.2 µM and 4.0 µM, for the two more potent compounds respectively, and for cell line SK-Mel-28 IC50 of 9.7 µM and 9.6 µM was obtained for PBZ01 and PBZ04, respectively. These compounds, alone or in combination with DTIC, were used to analyze the cumulative population doubling, in an attempt to simulate the treatment cycle used for patients. The results show that PBZs 1 and 4, especially when in combination with dacarbazine, were able to cause a significant decrease in the population growth rate and in the number of colonies in clonogenic assay, of the SK-Mel-28, better than dacarbazine alone and in lower concentration. Also, it is important to highlight that the effect of PBZs was selective to melanoma, considering that it did not cause relevant effect in melanocyte and in the proliferative nontumoral cell line, MRC5. The cell cycle analysis showed that the treatment alters the cell complexity, increasing the size (FSC) and granularity (SSC). Furthermore, when vemurafenib-resistant cells were treated with PBZ (cotreatment with vemurafenib), there were a population decrease in the population doubling assay more than vemurafenib alone. These results are important and encourage the study of the mechanism by which these compounds affect the melanomas9 viability as well as the development of a preclinical model to confirm their effectiveness in vivo. Citation Format: Jessica Goncalves Azevedo, Iago Carvalho Schultz, Jacqueline Fraga de Souza Santos, Silvya Stuchi Maria-Engler, Guido Lenz, Marcia Rosângela Wink. Pyrimidobenzimidazoles as a potential new drug to treat human melanoma [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; Sao Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr B34.