An allomaltol derivative triggers distinct death pathways in luminal a and triple-negative breast cancer subtypes

Abstract

Breast cancer is the most common cancer in women that shows a predisposition to metastasize to the distant organs. Kojic acid is a natural fungal metabolite exhibiting various biological activities. Compounds derived from kojic acid have been extensively studied and proved to demonstrate anti-neoplastic features on different cancer types. In the present study, allomaltol-structural analog of kojic acid and its seven derivatives including four novel compounds, have been synthesized, characterized and their possible impact on breast cancer cell viability was investigated. It was discovered that compound 5, bearing 3,4-dichlorobenzyl piperazine moiety, could decrease the viability of both MCF-7 and MDA-MB-231 cell lines distinctively. To ascertain the death mechanism, cells were subjected to different tests following the application of IC50 concentration of compound 5. Data obtained from lactate dehydrogenase activity and gene expression assays pointed out that necrosis had taken place predominantly in MDA-MB-231. On the other hand, in MCF-7 cells, the p53 apoptotic pathway was activated by overexpression of the pro-apoptotic TP53 and Bax genes and suppression of the anti-apoptotic Mdm-2 and Bcl-2 genes. Furthermore, Bax/Blc-2 ratio was escalated by 3.5 fold in the study group compared to the control. Compound 5 did not provoke drug resistance in MCF-7 cells since the Mdr-1 gene expression, drug efflux, and H2O2 content remained unaltered. As for MDA-MB-231 cells, only a 1.4 fold increase in the Mdr-1 gene expression was detected. These results indicate the advantage of the allomaltol derivative over the chemotherapeutic agents conventionally used for breast cancer treatment that can be highly toxic and mostly lead to drug resistance. Thus, this specific allomaltol derivative offers an alternative therapeutic approach for breast cancer which needs further investigation.