Abstract
The anticancer agent adriamycin (ADR) has long been recognized to induce a dose-limiting cardiotoxicity, while Salvia miltiorrhiza (SM) is a Chinese herb widely used for the treatment of cardiovascular disorders and its aqueous extract (SMAE) has shown anticancer as well as antioxidant effects. In the current study, we aimed at investigating the synergistic effect and potent molecular mechanisms of SMAE with a focus on the cardioprotective benefit observed under ADR adoption. Histopathological analysis indicated that SMAE could substantially alleviate cardiomyopathy and cell apoptosis caused by ADR. Meanwhile, the two-dimensional electrophoresis (2-DE) oxyblots demonstrated that SMAE treatment could effectively reduce carbonylation of specific proteins associated with oxidative stress response and various metabolic pathways in the presence of ADR. SMAE application also showed protective efficacy against ADR-mediated H9c2 cell death in a dose-dependent manner without causing any cytotoxicity and significantly attenuated the reactive oxygen species production. Particularly, the simultaneous administration of ADR and SMAE could remarkably suppress the growth of breast cancer cells. We also noticed that there was a marked upregulation of detoxifying enzyme system in the presence of SMAE, and its exposure also contributed to an increase in Nrf2 and HO-1 content as well. SMAE also amended the ERK/p53/Bcl-xL/caspase-3 signaling pathways and the mitochondrial dysfunction, which eventually attribute to apoptotic cathepsin B/AIF cascades. Correspondingly, both the ERK1/2 inhibitor (U0126) and pan-caspase inhibitor (Z-VAD-FMK) could at least partially abolish the ADR-associated cytotoxicity in H9c2 cells. Collectively, these results support that ROS apoptosis-inducing molecule release is closely involved in ADR-induced cardiotoxicity while SMAE could prevent or mitigate the causative cardiomyopathy through controlling multiple targets without compromising the efficacy of chemotherapy.
Highlights
The anthracycline antibiotic adriamycin (ADR), known as doxorubicin, is the commonly used chemotherapeutic agent for the treatment of various cancers
To further address the signaling events underlying the apoptotic response of H9c2 cells after exposure to ADR with or without Salvia miltiorrhiza aqueous extract (SMAE) application, we investigated the MAPK cascades which might trigger downstream signaling such as p53 pathway associated with apoptosis induction
The herbal medicine which has been widely used for heart protection or treatment of cancers may serve as a promising cardioprotective strategy against ADR-elicited cardiomyopathy [9, 29, 30]
Summary
The anthracycline antibiotic adriamycin (ADR), known as doxorubicin, is the commonly used chemotherapeutic agent for the treatment of various cancers. Our previous research has revealed that SMAE provides a protective effect against adriamycin- (ADR-) induced cardiomyopathy and hepatic damage [13]. The molecular pathways associated with the SMAE-mediated advantageous effect in managing the cardiotoxicity resulting from ADR treatment have not been thoroughly investigated. We used animal and cellular models to verify whether ADR-induced cardiomyopathy could be relieved by SMAE and evaluate the synergistic effect on cancer cells. ROS generation caused by ADR administration would disturb the normal redox balance and produce huge oxidative stress, which subsequently stimulates the carbonylation of specific groups of proteins involved in physiological dysfunction and induces cardiomyocyte apoptosis [14,15,16]. The present study has shed light on the cellular mechanisms involved with SMAE, exhibiting its protective effect and inhibition of ADR-induced cardiomyopathy.
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