SPOKANE, Wash.—One doesn’t usually think of cancer and cardiovascular disease at the same time, but there is reason to because of doxorubicin, a commonly used chemotherapy drug that can cause heart damage. But if researchers at Washington State University (WSU) have their way, we will be thinking of tumors and heart disease together even less, as they say that a protein called CDK2 is the culprit in doxorubicin-induced heart damage. Their findings were published recently in the Journal of Biological Chemistry.
Using a rodent model, the researchers showed that doxorubicin increases CDK2 activity in cardiac muscle cells, resulting in cell death, and they demonstrated that suppressing CDK2 levels alleviated damage to cardiac muscle cells following treatment with doxorubicin.
The researchers exposed a group of mice to doxorubicin and observed its effects on cardiac muscle cells and levels of CDK2 in those cells, as compared to control mice. Mice that received doxorubicin showed increased cardiac muscle cell death and elevated CDK2 activity in cardiac muscle cells, which came as a surprise.
“It has been known that chemotherapy decreases CDK activity in cancer cells and that this is involved in stopping tumor growth,” said study author Dr. Zhaokang Cheng, an assistant professor in the WSU College of Pharmacy and Pharmaceutical Sciences. “Interestingly, though, when we looked at CDK levels in the heart, chemotherapy increased CDK activity, which was the opposite of what scientists were thinking.”
So, while doxorubicin ceases cancer cell growth, it seems that it jumpstarts cardiac muscle cell growth. And because doxorubicin kills cancer cells by causing DNA damage, Cheng suggests that damaged DNA in multiplying cardiac muscle cells eventually causes those cells to stop replicating and die, weakening the heart. He said that could also explain why children—whose hearts are still growing—are more sensitive to heart toxicity from chemotherapy treatment.
So, the team went forward to the next step: examining whether inhibiting CDK2 could stop heart cell growth and protect the heart from doxorubicin-induced damage. They treated a group of mice with both doxorubicin and roscovitine—an immunosuppressive substance that selectively inhibits CDK2— and found that heart function in those mice was preserved. The same findings were also confirmed in rat heart cells.
The study shows early promise that CDK inhibitor drugs could be used to stave off heart toxicity in patients being treated with doxorubicin.
CDK inhibitors are a newer class of anticancer drugs. Only three such drugs—palbociclib, ribociclib and abemaciclib—are currently FDA-approved for the treatment of different types of breast cancers, while another dozen or so are being tested in clinical trials.
“Our findings suggest that combining doxorubicin with a CDK inhibitor could be a viable strategy for protecting patients’ hearts while they are being treated for cancer,” Cheng said. “It could provide a much stronger anticancer effect with less toxicity to the heart.”