Salinomycin (Sal), an ion-carrier antibiotic, effectively suppresses cancer growth and metastasis through autophagy or ferroptosis induction, thereby overcoming drug resistance. D4476, a selective inhibitor of casein kinase 1 alpha (CK1α), also inhibits the growth of tumors. However, their combined effect on colorectal cancer (CRC) cell growth and the mechanism underlying this effect remain unknown. This study evaluated the impact of Sal and D4476 on HCT116 CRC cells growth, ferroptosis, and autophagy by utilizing MTT assays, real-time PCR, Scratch Wound Healing Assay, reduced glutathione (GSH), and lipid peroxidation assays. It was discovered that Sal in combination with D4476 inhibited cell growth and triggered ferroptosis in a time- and dosage-dependent way, with nuclear factor E2-related factor 2 (NRF2) expression decreasing. Nevertheless, the level of phosphohydroxythreonine aminotransferase 1 (PSAT1) expression is higher in the Sal-D4476 combination compared to Sal alone. In addition, this combination resulted in a synergistic depletion of GSH and production of MDA, as well as an inhibition of autophagic flux by upregulating the gene expressions of Beclin1, LC3βII, and p62. In conclusion, the combination of Sal and D4476 suppressed the growth of HCT116 CRC cells by inducing ferroptosis and inhibiting autophagic flux. This research could lead to a novel method of using Sal in the clinic as a new antitumor drug, particularly when combined with other therapies that target the p62-NRF2 axis, such as D4476.

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