The phloroglucinol calcitrinone A, a novel mitochondria-targeting agent, induces cell death in breast cancer cells.

Citation:
El Gaafary, M., F. R. Saber, E. A. Mahrous, R. M. Ashour, M. O. N. A. M. OKBA, L. Jin, S. J. Lang, M. Schmiech, T. Simmet, and T. Syrovets, "The phloroglucinol calcitrinone A, a novel mitochondria-targeting agent, induces cell death in breast cancer cells.", Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association, vol. 162, pp. 112896, 2022.

Abstract:

Breast cancer is the most common cancer and the leading cause of cancer-related mortality among females worldwide. From the leaves of Callistemon citrinus, we have isolated a novel phloroglucinol dimer, calcitrinone A, and analyzed its potential anticancer activity using the triple-negative breast cancer cell line MDA-MB-231. Calcitrinone A decreased the total intracellular ATP levels, inhibited proliferation, and induced apoptosis in MDA-MB-231 cells, but was less toxic to peripheral blood mononuclear cells. The antiproliferative and apoptosis-inducing effects of calcitrinone A were confirmed in vivo using breast cancer xenografts grown on chick chorioallantoic membranes. Mechanistic analysis showed mitochondrial membrane-potential dissipation and interference with energy-yielding processes resulting in cell accumulation in the S phase of the cell cycle. Seahorse assay analysis revealed an early inhibition of mitochondrial oxidative phosphorylation (OXPHOS). At the molecular level, calcitrinone A inhibited activity of the succinate-coenzyme Q reductase (SQR) (mitochondrial complex II). In silico docking identified the coenzyme Q binding pocket as a possible high affinity binding site for calcitrinone A in SQR. Inhibition of complex II was accompanied by strong elevation of mitochondrial superoxide and cytoplasmic ROS. Calcitrinone A might be a promising anticancer lead compound acting through the interference with the mitochondrial complex II activity.

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