Switching the Mode of Cell Death between Apoptosis and Autophagy by Histone Deacetylase 6 Inhibition Levels

• Published in: ChemMedChem 2023-03, Vol.18 (5), p.e202200614-n/a
• Main Authors: Zhou, An‐Min, Wang, Meng‐Meng, Su, Yan, Yu, Zheng‐Hong, Liu, Hong‐Ke, Su, Zhi
• Format: Article
• Language: English
• Subjects: Anticancer properties; Antitumor activity; Apoptosis; Autophagy; Cancer; Caspase; Cell cycle; Cell Death; Cell Line, Tumor; Cervical cancer; Chloroquine; Damage accumulation; Deoxyribonucleic acid; DNA; HeLa Cells; Histone deacetylase; Histone Deacetylase 1; Histone Deacetylase 6; Histone Deacetylase Inhibitors - pharmacology; Histones; Humans; Inhibitors; Multicellular tumor spheroids; Spheroids; Switching; Valproic acid; Valproic Acid - pharmacology
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.202200614

Inhibition of histone deacetylase (HDAC) has been demonstrated to be an effective strategy for cancer treatment. In this work, we have developed a new agent Ir‐VPA, which exhibits the cell death mode switching between apoptosis and autophagy due to the distinct level of HDAC6 inhibition. Ir‐VPA indicates the best anticancer activity to HeLa cells, and could be hydrolyzed due to the high expression of the esterase in HeLa cells. Ir‐VPA could accumulate in nuclei, induce severe DNA damages and cell cycle arrest at G2/M phase. The anticancer mechanism of Ir‐VPA to HeLa cells was dependent on the HDAC6 inhibitory performance, as the caspase dependent apoptosis at low concentration (IC50) and autophagy with the autophagy flux blockage at high concentration (2×IC50). This is resulted from the distinct inhibitory levels of HDAC6, as moderate/complete inhibition at the concentration of IC50/2×IC50.In the presence of autophagic inhibitor chloroquine, the apoptotic population elevated from 32.7 % to 61.7 %, indicating that Ir‐VPA could activate apoptotic process through the autophagolysosome fusion inhibition. Ir‐VPA also exhibits excellent antiproliferative behavior to 3D HeLa multicellular tumor spheroids (MCTSs). This work not only provided a new HDAC6 inhibitor and novel anticancer mechanism for the effective treatment of cervical cancer, but also demonstrated the strategy to conjugate the metal fragment with active organic drug to enhance the anticancer performance. This work not only provided a new histone deacetylase (HDAC) 6 inhibitor with a novel mechanism of action against cancer cells, switching between apoptosis and autophagy, but also serves to demonstrate the strategy of conjugating a metal chelate with an active organic drug to enhance anticancer performance.