Calcium homeostasis and endoplasmic reticulum stress are involved in Salvianolic acid B-offered protection against cardiac toxicity of arsenic trioxide

Abstract

Arsenic trioxide (ATO) is a potent anticancer agent used to treat acute promyelocytic leukemia. However, its cardiotoxicity limits ATO’s widespread clinical use. Previous studies demonstrated that ATO may aggravate Ca2+ overload and promote endoplasmic reticulum stress (ERS). Salvianolic acid B (Sal B) is cardioprotective against ATO and enhances ATO’s anticancer activities. The present study assessed whether the Sal B protective effect was related to maintenance of Ca2+ homeostasis and inhibition of ER stress. Male BALB/c mice were injected with ATO or ATO+Sal B once a day via the tail vein for 2 weeks. We then detected the effects of Sal B in real time using adult rat ventricular cardiomyocytes in vitro using an IonOptix MyoCam system. Sal B treatment alleviated ATO-induced abnormal cardiac contractions and Ca2+ homeostasis imbalance. Sal B increased sarcoplasmic reticulum Ca2+-ATPase (SERCA) activity, regulated Ca2+ handling protein expression, and decreased expression of ERS proteins. Our results demonstrate that the cardioprotective effect of Sal B correlates with SERCA modulation, maintenance of Ca2+ homeostasis, and inhibition of ER stress. These findings suggest Sal B may ameliorate ATO cardiotoxicity during clinical application.

The Cardiotoxicity Induced by Arsenic Trioxide is Alleviated by Salvianolic Acid A via Maintaining Calcium Homeostasis and Inhibiting Endoplasmic Reticulum Stress

“…ATO is a potent treatment for APL; however, due to the cardiotoxicity of ATO, many patients with cancer are unable to receive more efficient treatment [18]. Previous research by our team has shown that salvianolic acid B (Sal B) had a protective effect against cardiotoxicity induced by ATO [19]. Subsequently we found that Sal A also suppresses ATO-induced cardiac dysfunction in vivo and in vitro.…”

“…Oxidative stress is widely considered as one of the main mechanisms underlying the toxicity of ATO [19]. We previously showed that Sal A decreased oxidative stress and intracellular ROS levels, and increased antioxidant enzyme activity against ATO in vitro [11].…”

Protective effects of salvianolic acid B against hydrogen peroxide‑induced apoptosis of human umbilical vein endothelial cells and underlying mechanisms

“…Therefore, the present study further examined the anti-atherosclerotic effects of Sal B and investigated the underlying mechanisms. Previous studies have confirmed that Sal B has anti-oxidative effects and eliminates superoxide anion radicals (O 2− ), thereby suppressing hydrogen peroxide (H 2 O 2 )-induced apoptosis (10,11). Another study indicated that Sal B promotes human umbilical vein endothelial cell (HUVEC) proliferation (12).…”

The ER Stress Inducer l-Azetidine-2-Carboxylic Acid Elevates the Levels of Phospho-eIF2α and of LC3-II in a Ca2+-Dependent Manner

“…ER stress itself is intimately linked to intracellular Ca 2+ handling [8,9,10,11,12,13,14]. Treatment of cells with thapsigargin (TG) or cyclopiazonic acid, inhibitors of the sarco/endoplasmic Ca 2+ ATPase (SERCA), leads to ER Ca 2+ depletion and ER stress [15,16,17,18].…”