Schisandrin B Prevents Doxorubicin-Induced Cardiotoxicity via Enhancing Glutathione Redox Cycling

Abstract

Purpose: The dose-cumulative cardiotoxicties and the emerging cancerous apoptotic/drug resistance are two major obstacles limiting the efficacy of anthracycline antibiotics, notably doxorubicin. We attempted to prove if schisandrin B (Sch B), a dual inhibitor of P-glycoprotein and multidrug resistance^associated protein 1, could protect against doxorubicin-induced cardiotoxicity, on the premise that Sch B is an enhancer of glutathione redox cycling that may attenuate doxorubicin-induced oxidative stress in the cardiomyocytes. Experimental Design: Mice or rat were dosed with a single injection of doxorubicin (25 mg/kg, i.p.) with or without pretreatment of Sch B. The protective roles of Sch B against doxorubicininduced cardiac damage were evaluated on the aspects of the release of cardiac enzymes into serum, the formation of malondialdehyde, the activation of matrix metalloproteinase, the structural damage in the left ventricles, the mortality rates, and the cardiac functions. Results: Pretreatment of Sch B significantly attenuated doxorubicin-induced cardiotoxicities on all the aspects listed above. The underlying mechanism was associated with the effect of Sch B on maintaining the cardiomyocytic glutathione and the activities of superoxide dismutase, and the key enzymes (glutathione peroxidase, glutathione reductase, and glutathione transferase) responsible for glutathione redox cycling, which neutralized doxorubicin-induced oxidative stress. Conclusion: To the best of our knowledge, Sch B is the only molecule ever proved to function as a cardioprotective agent as well as a dual inhibitor of P-glycoprotein and multidrug resistanceâ ssociated protein 1, which is potentially applicable to treat cancers, especially the multidrugresistant cancers involving doxorubicin or its kin.

235 Schisandrin B prevents doxorubicin-induced chronic cardiotoxicity and enhances its anticancer activity in vivo

“…This communication, combined with our previous reports [13,16,17,18,22,23], provides evidence that Sch B can protect Dox-induced acute and chronic cardiotoxicity and enhancing its anticancer activity.…”

“…We have demonstrated that Sch B was a dual inhibitor of P-glycoprotein and multidrug-resistance associated protein, and thus could sensitize drug-resistant cells to many structurally and functionally unrelated drugs including anthracycline antibiotics as the substrates of the 2 drug pumps [13,16,17,18]. We also demonstrated that Sch B enhanced Dox anticancer activities in vivo against KBv200 (a human epidermoid carcinoma cell line overexpressing P-glycoprotein inoculated s.c. in nude mice) [19].…”

“…Baill, can protect against oxidative stress including carbon tetrachloride-induced hapatotoxicity [9], myocardical ischemia/reperfusion injury [10,11], and brain oxidative damage [12], through upregulation of GSH redox cycling. We recently demonstrated that Sch B was able to prevent Dox-induced acute cardiotoxicity, via enhancing cardiomyocytic glutathione redox cycling that could remove excessive ROS generated from Dox [13,14]. Nevertheless, we do not know if this compound is also effective in preventing Dox-induced chronic toxicity.…”

Schisandrin B, a Lignan from Schisandra chinensis Prevents Cerebral Oxidative Damage and Memory Decline Through Its Antioxidant Property

“…Further in in-vitro model Sch B elicits a glutathione antioxidant response and protects against apoptosis via the redox-sensitive ERK/Nrf2 pathway in AML12 heptocytes. (Leong, Chiu et al 2011) Sch B treatment increases antioxidant status of the heart and improves cardiac function against the adiramycin, doxorubicin and ischemia/reperfusion induced cardiac dysfunction (Li, Pan et al 2007;You, Pan et al 2006;Chiu and Ko 2004). It has been reported that Sch B enhances renal mitochondrial antioxidant status and protects against gentamicin-induced nephro-toxicity in rats.…”

Protective effect of ocotillol against doxorubicin-induced acute and chronic cardiac injury

“…The exact molecular mechanisms, however, in which reactive oxygen species (ROS) are considered to be central remain unclear (1,5). It was reported that Dox has been observed to transform into a semiquinone radical, which then reduces oxygen to produce superoxide and reacts with polyunsaturated fatty acids to yield lipid hydroperoxide (6). The antioxidants, which cleaved the generated ROS, were hypothesized to exhibit protective effects against Dox-induced cardiomyopathy (7,8).…”