Anti-cancer drugs for cardioprotection

Cardiovascular disease and cancer are the first and second common cause of death globally. An estimated 17.5 million people died from cardiovascular disease and 8.2 million died from cancer in 2012 according to the reports from World Health Organization (WHO). Although cardiovascular disease and cancer are regarded as 2 entirely different diseases before, recent studies suggest that these 2 diseases may share common risk factors, such as obesity, diabetes and chronic inflammation.¹ In addition, certain agents used for cancer therapies have been known to cause cardiotoxicity in the oncology patients. Thus, medications that have both anti-cancer and cardioprotective properties are urgently needed. Moreover, the potential biological mechanisms accounting for both diseases warrant more comprehensive study. To address this issue, we therefore thought of the potential application of certain anti-cancer agents on cardiovascular disease therapy.

Recent study from our group has revealed that an extract from medical mushroom Ganodermataceae, namely Ganoderma spore oil, exerts promising cardioprotective effects in both in vitro and in vivo models.² Ganoderma lucidum has been widely prescribed to cancer patient as a complementary treatment alongside chemo/radiotherapy in Asia. In this study, mice with heart failure modeling by transverse aortic constriction (TAC) were administered Ganoderma spore oil for 14 days. TAC mice with the Ganoderma treatment were found to have an elevated left ventriclular ejection fraction (LVEF) and left ventriclular fractional shortening (LVFS) as well as a reduced left ventricular end diastolic diameter (LVEDD) compared to mock treated TAC mice with vegetable oil. Moreover, Ganoderma spore oil administration also restored the cardiac output of TAC mice to the physiologic levels. These results indicated that Ganoderma is able to improve the cardiac function of TAC mice. Ganoderma lucidum is a genus of a well-studied traditional medical mushroom family Ganodermataceae, which contains a number of bioactive components including polysaccharides, ganoderic acid (triterpene) and adenosine. Ganoderma lucidum and another member of the Ganodermataceae family, Amauroderma rude, are well-known for their anti-cancer activities which include inhibiting cell proliferation and inducing cell apoptosis.^3,4 Ergosterol peroxide, purified from Ganoderma lucidum, has been found to effectively induce cancer cell death and suppress cell migration, cell cycle progression and colony formation in human hepatocellular carcinoma cells.³ Meanwhile, ergosterol purified from Amauroderma rude is able to accelerate cell apoptosis in breast cancer, and suppress malignant cell behaviors, such as cancer cell migration, invasion and colony formation.⁴ In several animal models, ergosterol was validated to prolong survival of the mice injected with murine melanoma cell line,⁴ activate immune cell activity and inhibit tumor growth of the mice injected with murine breast cancer cell line.⁵ It was confirmed in our recent findings that these medical components used for inhibiting cancer growth can improve cardiac function. Our results suggest that certain anti-cancer agents have the potential to be clinically employed as cardioprotective agents.

With respect to the fact that Ganoderma lucidum has dual therapeutic effects of anti-cancer and cardioprotection, we hypothesized that such effects might be mediated via shared biological mechanisms of these 2 diseases. Non-coding RNAs might be the fascinating candidates, which serve as key mediators for Ganoderma lucidum against both cancer and heart failure. The microRNA and circular RNA are 2 of the major types of non-coding RNAs. Our previous study unraveled that ergosterol peroxide isolated from Ganoderma lucidum induced cell death by abolishing microRNA miR-378-mediated tumor cells on chemoresistance.⁶ In addition to microRNAs, our recent study also validated that the cardioprotective effect of Ganoderma lucidum is mediated by a circular RNA circ-Foxo3 encoded by the Foxo3 gene.² Increased expression of circ-Foxo3 RNA has also been found in mice with reduced cardiac function.⁷ In an in vitro study, Ganoderma spore oil treatment significantly reduced the level of circ-Foxo3 in mouse cardiac fibroblasts subjected to H₂O₂-induced oxidative stress. In line with the in vitro findings, the circ-Foxo3 levels were also found to be significantly decreased in the heart tissues of TAC mice after Ganoderma spore oil administration compared to mock group.² Collectively, the above results from our group suggest that microRNA and circular RNA, especially circ-Foxo3, may play an important role in mediating both anti-cancer and cardioprotective effect of Ganoderma.

In the past decades, non-coding RNAs gained extensive attention due to their diverse roles in a variety of diseases. Especially, research interest toward circular RNA is growing since there is increasing evidence of their roles in gene regulation and disease progression. The acknowledgment that circular RNAs play dual roles against both cancer and cardiovascular disease will raise a new perspective to further understand the shared mechanisms of the progression between these 2 diseases. Our pre-clinic study also provides an implication of using non-chemotherapy anti-cancer medication to protect cardiac function. Ultimately, this may benefit the patients suffering from cardiovascular toxicity due to chemotherapy.

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.

Funding

Our studies were supported by The High-Level Leading Talent Introduction Program of GDAS (2016GDASRC-0102), The Introduction of Leading Talent Project of Guangdong Province, and Guangdong Key Technology Program (2012A020100010).