New Insights into the anticancer effects of two ?-lapachone derivatives on solid tumors cells

New Insights into the anticancer effects of two ?-lapachone derivatives on solid tumors cells

• Author
• José Rivaldo de Lima
• Co-authors
• Elizabeth Fernanda de Oliveira Borba , George Torres de Lima , Abner Lins Dantas , Elayne Rayane Diniz Melo , Mariza Severina de Lima Silva , Alexandre José da Silva Góes , Teresinha Gonçalves da Silva
• Abstract

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  INTRODUCTION: ?-lapachone (?-lap) is a naphthoquinone known for its anticancer properties but accompanied by high toxicity [1, 2]. Presently, ongoing research is focused on the exploration of novel ?-lap derivatives for cancer chemotherapy with reduced toxicity levels [3, 4]. Recently, the ?-lap derived compounds 2-(2,2-dimethyll-5-oxo-3,4-dihydro-2H-benzo[h]chrome-6(5H)-ylidene)-N-(4-nitrophenyl)-hydrazinecarbothioamide (BV3) and 2-(2,2-dimethyl-5-oxo-3,4-dihydro-2H-benzo-[h]chromo-6(5H)-ylidene)-N-(ptolulu) hydrazinecarbothioamide (BV5), have been proven their antileukemic activities. These compounds exhibited cytotoxicity and selectivity towards cancer cells. However, no studies have been conducted to investigate the action of these compounds on solid tumor cells, which have been the primary target of ?-lapachone [4]. AIMS: The objective of this study was to explore the cytotoxic potential in solid tumors and elucidate the cellular death mechanism of BV3 and BV5. METHODS: The cytotoxicity of the compounds was evaluated in L-929 (murine fibroblast), HeLa (human cervical adenocarcinoma), HCT-116 (human colorectal carcinoma), HepG2 (human hepatocellular carcinoma) and MDA-MD-231 (mammary gland adenocarcinoma) by the method of MTT [5]. To assess signs of cellular demise, changes in cell morphology were observed through optical microscopy, and the mechanism of cell death was investigated using flow cytometry in HeLa cells. RESULTS AND DISCUSSION: The results indicate that BV3 and BV5 derivatives have anticancer activity against HCT-116, HepG2, and MDA-MD-231 cell lines, with IC₅₀ values lower than 15 ?g/mL. For HeLa cell line, the BV3 and BV5 compounds showed a remarkable IC₅₀ of 1.21 ?g/mL and 7.21 ?g/ml, respectively. Also, the IC₅₀ for the L-929 was 19.19 ?g/mL for BV3 and 5.33 for BV5, at 72 h of incubation. We observed a high selectivity for BV3 againt HeLa cell line. From these data, the HeLa lineage was chosen to continue the tests because it showed better IC₅₀ and selectivity index results. Moreover, IC₅₀ values were investigated at 24 h and 48 h for the mechanism of action tests. As a result, BV3 exhibited IC₅₀ of > 25 and 10.26 ?g/mL, while BV5 showed IC₅₀ of > 25 and 9.95 ?g/mL at 24 and 48 h of incubation, respectively. Therefore, it was observed through optical microscopy that these derivatives cause morphological changes typical of apoptosis in the concentrations of IC₅₀ and 2 x IC₅₀. In the analysis by flow cytometry, the cell death mechanism of these derivatives on HeLa cells in inducing death by apoptosis/necrosis was confirmed. CONCLUSION: The BV3 derivative showed antineoplastic activity in vitro for the strains tested, with high selectivity for the HeLa cells, acting through the induction of apoptosis/necrosis. ACKNOWLEDGEMENT: We thank Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) for the scholarship awarded to José R. Lima (Funding Code 88887.636741/2021-00).

   

   

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• Keywords
• Naphthoquinone, Apoptosis, Necrosis.
• Modality
• Pôster
• Subject Area
• Drug Design and Discovery, Synthesis and Natural Products