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

Menna El Gaafary; Fatema R Saber; Engy A Mahrous; Rehab M Ashour; Mona M Okba; Lu Jin; Sophia J Lang; Michael Schmiech; Thomas Simmet; Tatiana Syrovets

doi:10.1016/j.fct.2022.112896

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

Food Chem Toxicol. 2022 Apr:162:112896. doi: 10.1016/j.fct.2022.112896. Epub 2022 Feb 25.

Authors

Affiliations

¹ Department of Pharmacognosy, College of Pharmacy, Cairo University, Cairo, 11562, Egypt; Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University, 89081, Ulm, Germany.
² Department of Pharmacognosy, College of Pharmacy, Cairo University, Cairo, 11562, Egypt.
³ Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University, 89081, Ulm, Germany.
⁴ Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University, 89081, Ulm, Germany. Electronic address: thomas.simmet@uni-ulm.de.
⁵ Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University, 89081, Ulm, Germany. Electronic address: tatiana.syrovets@uni-ulm.de.

PMID: 35227860
DOI: 10.1016/j.fct.2022.112896

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.

Keywords: Breast cancer; Callistemon citrinus; Mitochondrial complex II; Phloroglucinol; ROS; Succinate dehydrogenase; Succinate:ubiquinone oxidoreductase.