Publication: Exploring the anticancer effects of brominated plastoquinone analogs with promising cytotoxic activity in MCF-7 breast cancer cells via cell cycle arrest and oxidative stress induction
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2022-06-01
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Abstract
Plastoquinone analogs are privileged structures among the known antiproliferative natural product-based compound families. Exploiting one of these analogs as a lead structure, we report the investigation of the brominated PQ analogs (BrPQ) in collaboration with the National Cancer Institute of Bethesda within the Developmental Therapeutics Program (DTP). These analogs exhibited growth inhibition in the micromolar range across leukemia, non-small cell lung cancer (EKVX, HOP-92, and NCI-H522), colon cancer (HCT-116, HOP-92), melanoma (LOX IMVI), and ovarian cancer (OVCAR-4) cell lines. One brominated PQ analog (BrPQ5) was selected for a full panel five-dose in vitro assay by the NCI’s Development Therapeutic Program (DTP) division to determine GI50, TGI, and LC50parameters. The brominated PQ analog (BrPQ5) displayed remarkable activity against most tested cell lines, with GI50values ranging from 1.55 to 4.41 µM. The designed molecules (BrPQ analogs) obeyed drug-likeness rules, displayed a favorable predictive Absorption, Distribution, Metabolism, and Excretion (ADME) profile, and an in silico simulation predicted a possibleBrPQ5interaction with proteasome catalytic subunits. Furthermore, the in vitro cytotoxic activity ofBrPQ5was assessed, and IC50values for U-251 glioma, MCF-7 and MDA-MB-231 breast cancers, DU145 prostate cancer, HCT-116 colon cancer, and VHF93 fibroblast cell lines were evaluated using an MTT assay. MCF-7 was the most affected cell line, and the effects ofBrPQ5on cell proliferation, cell cycle, oxidative stress, apoptosis/necrosis induction, and proteasome activity were further investigated in MCF-7 cells. The in vitro assay results showed thatBrPQ5caused cytotoxicity in MCF-7 breast cancer cells via cell cycle arrest and oxidative stress induction. However,BrPQ5did not inhibit the catalytic activity of the proteasome. These results provide valuable insights for further discovery of novel antiproliferative agents.
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Tıp, Temel Eczacılık Bilimleri, Eczacılık, Sağlık Bilimleri, Temel Tıp Bilimleri, Medicine, Basic Pharmaceutics Sciences, Pharmacology and Therapeutics, Health Sciences, Fundamental Medical Sciences, Klinik Tıp (MED), Yaşam Bilimleri (LIFE), Klinik Tıp, Farmakoloji ve Toksikoloji, TIP, GENEL & DAHİLİ, FARMAKOLOJİ VE ECZACILIK, Clinical Medicine (MED), Life Sciences (LIFE), CLINICAL MEDICINE, PHARMACOLOGY & TOXICOLOGY, MEDICINE, GENERAL & INTERNAL, PHARMACOLOGY & PHARMACY, Genel Sağlık Meslekleri, Farmakoloji, Farmakoloji, Toksikoloji ve Eczacılık (çeşitli), Genel Farmakoloji, Toksikoloji ve Eczacılık, Patofizyoloji, Temel Bilgi ve Beceriler, Değerlendirme ve Teşhis, Farmakoloji (tıbbi), Dahiliye, Aile Sağlığı, İlaç Rehberleri, Tıp (çeşitli), Genel Tıp, Yaşam Bilimleri, Pharmacy, General Health Professions, Pharmacology, Pharmacology, Toxicology and Pharmaceutics (miscellaneous), General Pharmacology, Toxicology and Pharmaceutics, Pathophysiology, Fundamentals and Skills, Assessment and Diagnosis, Pharmacology (medical), Internal Medicine, Family Practice, Drug Guides, Medicine (miscellaneous), General Medicine, Life Sciences, quinone, plastoquinones, antiproliferative activity, cytotoxicity, cell cycle, oxidative stress, ADME, DRUG DISCOVERY, PROTEASOME, DERIVATIVES, INSTITUTE
Citation
Jannuzzı A. T., Yılmaz Göler A. M., Bayrak N., Yıldız M., Yıldırım H., Yılmaz B., Shilkar D., Jayaprakash Venkatesan R., Jayaprakash V., Tuyun A. F., "Exploring the Anticancer Effects of Brominated Plastoquinone Analogs with Promising Cytotoxic Activity in MCF-7 Breast Cancer Cells via Cell Cycle Arrest and Oxidative Stress Induction", Pharmaceuticals, cilt.15, ss.777-799, 2022