Structure-activity relationship of anticancer drug candidate quinones.

Breast cancer is one of the most prevalent cancer types worldwide. Chemotherapy is a substantial approach in the management of breast cancer despite the occurrence of chemotherapy-associated side effects and the development of multidrug resistance in cancer cells. At this point, a variety of quinone derivatives may represent potential as possible anticancer drug candidates due to possessing structural similarity towards clinically used anticancer drugs like doxorubicin. Therefore, we investigated the cytotoxic effects of various quinone derivatives with structural diversity towards a variety of breast cancer cells. We further determined their toxicity in healthy cells to evaluate their drug capability potential. Eighteen quinone derivatives (arbutin, hydroquinone, alkannin, lapachol, lawsone, juglone, aloe-emodin, aloin, cascaroside A (8-O-ß-D-glucoside of 10-C-ß-D-glucosyl aloe-emodin anthrone), chrysophanol, chrysophanol-8-O-ß-D-glucoside, emodin, emodin-8-O-ß-D-glucoside, frangulin A (emodin-6-O-a-L-rhamnoside), physcion, rhein, sennoside A, sennoside B (sennoside A and sennoside B are stereoisomers and rhein-dianthrone diglycosides in which ß-D-glucose units are bound to the OH groups of rhein anthrones at their 8th positions) were tested on MCF-7, SK-BR-3, MDA-MB-468, and MDA-MB-231 breast cancer cells and on H9c2 healthy rat cardiac myoblast cells in terms of their cytotoxicity and toxicity, respectively. The resazurin reduction assay was used to determine the cytotoxicity. Among the tested compounds, two naphthoquinone derivatives alkannin and juglone exhibited remarkable cytotoxicity on breast cancer cells and exhibited alleviated toxicity profiles on healthy cells deserving further investigation as possible drug candidates against breast cancer. Structure-activity relationships of these compounds were also evaluated and discussed. Alkannin and juglone, which are naphthoquinone derivatives isolated from natural sources, may be promising agents in the development of drug-candidate molecules with increased efficacy and safety for breast cancer.

Cytotoxic naphthoquinones from Arnebia densiflora (Nordm.) Ledeb and determining new apoptosis inducers.

In this study, phytochemical composition of Arnebia densiflora (AD) was determined and cytotoxic effects of the n-hexane extract and compounds isolated from this species on various cell lines were investigated. By means of serial chromatographic studies, 6 naphthoquinone derivatives were yielded, which are isovalerylalkannin, α-methyl-n-butyl alkannin, acetylalkannin, ß-acetoxy isovalerylalkannin, alkannin and a new compound: 4-hydroxy 4-methyl valeryl alkannin. Structures of the isolated compounds were elucidated using UV, IR, 1D-2D NMR, MS and CD methods. Cytotoxic effects of the extract and isolated alkannins were investigated on L929, HeLa, HEp-2 cells. AD and the isolated compounds demonstrated moderate to strong cytotoxic effects (IC50 range: 4.92-172.35 µg/ml). The results of DNA fragmentation and caspase-3 activity studies on HeLa cells exhibited that AD and the naphthoquinones isolated from it caused cytotoxicity through induction of apoptosis.[Formula: see text].

BMPRII deficiency impairs apoptosis via the BMPRII-ALK1-BclX-mediated pathway in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a devastating cardiovascular disorder characterized by the remodelling of pre-capillary pulmonary arteries. The vascular remodelling observed in PAH patients results from excessive proliferation and apoptosis resistance of pulmonary arterial smooth muscle cells (PASMCs) and pulmonary arterial endothelial cells (PAECs). We have previously demonstrated that mutations in the type II receptor for bone morphogenetic protein (BMPRII) underlie the majority of the familial and inherited forms of the disease. We have further demonstrated that BMPRII deficiency promotes excessive proliferation and attenuates apoptosis in PASMCs, but the underlying mechanisms remain unclear. The major objective of this study is to investigate how BMPRII deficiency impairs apoptosis in PAH. Using multidisciplinary approaches, we demonstrate that deficiency in the expression of BMPRII impairs apoptosis by modulating the alternative splicing of the apoptotic regulator, B-cell lymphoma X (Bcl-x) transcripts: a finding observed in circulating leukocytes and lungs of PAH subjects, hypoxia-induced PAH rat lungs as well as in PASMCs and PAECs. BMPRII deficiency elicits cell specific effects: promoting the expression of Bcl-xL transcripts in PASMCs while inhibiting it in ECs, thus exerting differential apoptotic effects in these cells. The pro-survival effect of BMPRII receptor is mediated through the activin receptor-like kinase 1 (ALK1) but not the ALK3 receptor. Finally, we show that BMPRII interacts with the ALK1 receptor and pathogenic mutations in the BMPR2 gene abolish this interaction. Taken together, dysfunctional BMPRII responsiveness impairs apoptosis via the BMPRII-ALK1-Bcl-xL pathway in PAH. We suggest Bcl-xL as a potential biomarker and druggable target.