Discovery of a novel ferroptosis inducer-talaroconvolutin A—killing colorectal cancer cells in vitro and in vivo

Abstract

Ferropotsis is among the most important mechanisms of cancer suppression, which could be harnessed for cancer therapy. However, no natural small-molecule compounds with cancer inhibitory activity have been identified to date. In the present study, we reported the discovery of a novel ferroptosis inducer, talaroconvolutin A (TalaA), and the underlying molecular mechanism. We discovered that TalaA killed colorectal cancer cells in dose-dependent and time-dependent manners. Interestingly, TalaA did not induce apoptosis, but strongly triggered ferroptosis. Notably, TalaA was significantly more effective than erastin (a well-known ferroptosis inducer) in suppressing colorectal cancer cells via ferroptosis. We revealed a dual mechanism of TalaA’ action against cancer. On the one hand, TalaA considerably increased reactive oxygen species levels to a certain threshold, the exceeding of which induced ferroptosis. On the other hand, this compound downregulated the expression of the channel protein solute carrier family 7 member 11 (SLC7A11) but upregulated arachidonate lipoxygenase 3 (ALOXE3), promoting ferroptosis. Furthermore, in vivo experiments in mice evidenced that TalaA effectively suppressed the growth of xenografted colorectal cancer cells without obvious liver and kidney toxicities. The findings of this study indicated that TalaA could be a new potential powerful drug candidate for colorectal cancer therapy due to its outstanding ability to kill colorectal cancer cells via ferroptosis induction.

Development and validation of a ferroptosis-related lncRNAs prognosis signature in colon cancer

“…Consequently, the role of molecular biomarkers prognosis is of particular importance [17]. Ferroptosis was involved in COAD migration, invasion, proliferation, and other biological behaviour [6,7].…”

“…Regulate ferroptosis in tumor cells is a novel treatment modality [5]. Increasing evidence supports that ferroptosis participates in the pathophysiology of COAD [6][7][8]. Thus, identifying critical regulators of ferroptosis is an essential step towards a more in-depth understanding.…”

Ferroptosis-Related Gene Signature and Patterns of Immune Infiltration Predict the Overall Survival in Patients With Lung Adenocarcinoma

“…Silencing TXNRD1 was proven to enhance cytotoxicity of triple-negative breast cancer cells (Chepikova et al, 2020). Upregulated arachidonate lipoxygenase 3 (ALOXE3) can promote ferroptosis in colorectal cancer (Xia et al, 2020). Iron metabolism is regulated by phosphorylase kinase G2 (PHKG2) and cysteine dioxygenase 1 (CDO1), which leads to ferroptosis (Yang et al, 2016;Hao et al, 2017).…”

Regulated Necrotic Cell Death in Alternative Tumor Therapeutic Strategies

“…A diazepin-quinazolin-amine derivative BIX-01294 enhanced GSDME-mediated pyroptosis in human gastric adenocarcinoma cell lines [ 152 ]. Talaroconvolutin isolated from the endophytic fungus Talaromyces wortmanni caused ferroptosis in human colorectal cancer in vitro and in vivo [ 153 ]. However, the number of clinical studies on the use of the induction of RNCDs in cancer patients is very limited, and additional investigation and clinical trials are required.…”