Renieramycin t derivative dh_22 induces apoptosis in lung cancer cells by downregulation of C-Myc protein

Abstract

Lung cancer is a prevalent cause of death, indicated by an elevated c-Myc level. We synthesized a new derivative of renieramycin T (RT), named DH_22, and tested it for anti-cancer activities in human lung cancer cells. In the cell viability and nuclear staining tests, DH_22 was discovered to be cytotoxic, with an IC50 of around 13 μM; and found to mediate apoptosis in the lung cancer cells. Meanwhile, in a mechanistic sense, DH_22 contributed to the activation of p53-dependent apoptosis and decreased the cellular level of c-Myc. The p53-dependent mechanism was indicated by an increase of p53, an induction of the pro-apoptotic Bax protein, and a decrease of the anti-apoptotic B-cell lymphoma 2 (Bcl-2) protein. The fluorescence intensity of Akt, p-Akt, and c-Myc also declined significantly. Akt and p-Akt were detected in the cytoplasm and nucleus, while most of c-Myc was located in the nucleus of the untreated control cells. These results demonstrated that DH_22 could reduce c-Myc, supported by molecular docking. The mechanism of action of renieramycin T derivative DH_22 starts with the inhibition of mTOR, which reduces the phosphorylation of Akt, which then reduces the phosphorylation of GSK3b and accelerates the degradation of c-Myc. In addition, DH_22 itself could inhibit Akt via allosteric inhibition, which could disrupt the c-Myc stabilization.