Molecular functional evaluation of novel c-myc targeting anticancer compounds in non-small cell lung cancer and colon cancer cells

Abstract

The c-Myc protein is a key regulator of cell growth, proliferation, and differentiation. Its overexpression or dysregulation is linked to several cancers, including non-small cell lung cancer (NSCLC) and colorectal cancer (CRC). Here, we described ECD, a novel small molecule targeting c-Myc, which disrupts the c-Myc/MAX complex and induces c-Myc degradation in CRC cells. Anticancer activity of ECD includes cytotoxic effects through DNA damage and apoptosis, confirmed by whole-proteome profiling and a chick embryo xenograft assay. Autophagy, a mechanism for eliminating damaged organelles and proteins, can lead to apoptosis. This study showed 24MD induces autophagy in lung cancer cells, evidenced by autophagosome formation and upregulation of ATG5, ATG7, and p62. After 24 hours, LC3-I was converted to LC3-II, and p62 was downregulated. Apoptosis was observed after 48 hours. Mechanistically, 24MD downregulated p-mTOR, p-PI3K, and p-Akt. Combination with rapamycin enhanced mTOR suppression and LC3 activation. Structural modifications of similar compounds affected their mode of action. Cellular senescence can lead to chemotherapy resistance through GRP78. H460 cells treated with cisplatin developed senescence, showing increased mRNA and protein levels of p21 and p53 and decreased c-Myc levels. Senescent cells also exhibited higher levels of stemness markers CD44, CD133, Nanog, Oct4, and Sox2. Conventional chemotherapies were less effective in senescent cells, while benzoxazine derivatives maintained their cytotoxic profile. In summary, ECD targets c-Myc for potential CRC treatment, 24MD targets autophagic cell death by affecting mTOR-mediated autophagy, and benzoxazine derivatives show promise in treating therapy-induced senescent cells.