NSC777201 exhibits anticancer activity against colorectal cancer cells by inducing multiple types of cell death

Colorectal cancer (CRC) ranks as the third most prevalent cancer globally, necessitating the development of novel therapeutic strategies. NSC777201, a multi-targeted anticancer agent, has demonstrated efficacy in various cancers, including prostate cancer, non-small cell lung cancer (NSCLC), glioblastoma (GBM), and pancreatic ductal adenocarcinoma (PDAC). However, its potential in CRC remains unexplored. In this study, National Cancer Institute (NCI)-60 cancer cell panel screening identified CRC as the most sensitive to NSC777201 treatment. We further validated its in vitro anticancer effects in four CRC cell lines (HCT116, HT29, RKO, and DLD-1) and its in vivo efficacy using HCT116 tumor xenografts in nude mice. Mechanistic studies included analyses of epidermal growth factor receptor (EGFR) and MET protein inhibition and investigations into cell death pathways triggered by NSC777201. NSC777201 exhibited potent in vitro and in vivo anticancer activities against human CRC cells. NSC777201 inhibited expressions of the EGFR and MET proteins in CRC cells, consistent with findings in other cancers. Mechanistic studies revealed that NSC777201 induced CRC cell death through autophagy, ferroptosis, and ferritinophagy. Moreover, NSC777201-induced ferroptosis was partially dependent on upregulation of 7-dehydrocholesterol (DHC) reductase (DHCR7) and subsequent reduction of the endogenous ferroptosis suppressor, 7-DHC. These findings highlight NSC777201’s robust anticancer activity in CRC, mediated by multiple cell death pathways, offering promising therapeutic potential for CRC treatment.