Researchers have found that the blood pressure drug lacidipine can potentially double as a treatment for triple-negative breast cancer, a particularly hard-to-treat form of the disease.

Although only around 10% of breast cancer cases are triple negative, it’s the most aggressive form, often diagnosed at late stages and more likely to spread to other parts of the body or return after initial treatment. The disease is notoriously difficult to treat due to its resistance to conventional chemotherapy drugs and unresponsiveness to hormonal therapy.

“Clinical trials combining chemotherapy with targeted drugs have failed to show significant improvements in survival,” said Fei Wang, a professor at the Center for Natural Products Research at the Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, China. This lack of progress has led researchers to explore alternative treatments to help save lives.

Wang and his team wondered if blood pressure medications, which have been shown to inhibit colorectal cancer and skin cancer, could be repurposed to treat triple-negative breast cancer.

“Hypertension and cancer morbidity share the same biological pathways,” Wang explained, suggesting that drugs designed to regulate blood pressure might also have an impact on cancer cells by interfering with the metabolic pathways that allow tumors to grow and spread.

This new approach could open the door to more effective treatments for this difficult cancer, particularly in cases where conventional therapies have failed.

The link between calcium channels and cancer development

Antihypertensive drugs, such as nifedipine and amlodipine, lower blood pressure by restricting the supply of calcium to muscle cells in the walls of blood vessels. Calcium is needed for muscle cell contraction, so by blocking its entry, these drugs help relax and widen the blood vessels, making it easier for blood to flow. For this reason, blood pressure meds are also known as calcium channel blockers.

Interestingly, this mechanism may also have relevance for cancer treatment. “Dysfunction of calcium channels is closely related to the development and progression of cancer,” said Yuwen Sheng, a postdoctoral researcher at the Chengdu Institute of Biology who was also involved in the study.

Another critical process in cancer progression involves the amino acid tryptophan, which, when broken down as usual in the liver, produces kynurenine — a molecule that fuels tumor development.

“Dysregulated tryptophan metabolism can foster a chronic inflammatory environment that promotes tumor progression,” Wang explained.

It turns out that calcium channels may influence this process. Wang and his team discovered that calcium channels play a role in regulating tryptophan metabolism, linking them to tumor immunity and cancer progression.

“Our study is the first to reveal the previously unknown role of calcium channels in tryptophan metabolism-mediated tumor immunity,” Wang said, providing new insights into the complex relationship between hypertension and cancer growth.

Transforming cold tumors into hot tumors

Triple negative breast cancer is so difficult to treat because it lacks common markers, like the estrogen receptor, targeted by typical chemo treatments. Patients often have a lower survival rate, a higher chance of the cancer spreading, and a higher risk of relapse.

Cancer tumors are often classified as “cold” or “hot” depending on the level of immune system involvement. “Hot” tumors have a high presence of immune cells called tumor-infiltrating lymphocytes (TILs), which actively target and fight the cancer.

These tumors produce a strong inflammatory response, allowing the immune system to recognize and attack cancer cells more effectively, Wang explained. This is a more favorable scenario, as tumors with abundant TILs are associated with a better prognosis, thanks to the immune system’s efforts to control and eliminate the cancer.

“Transforming cold tumors into hot tumors is a crucial strategy for enhancing the effectiveness of cancer immunotherapy,” said Wang. This means boosting the immune system’s ability to fight the cancer, making immunotherapy more effective.

Triple-negative breast cancer is challenging to treat using immunotherapy drugs because the tumors are typically “cold”.

“This transformation [of cold tumors into hot tumors] not only broadens the range of tumors that can benefit from immunotherapy but also provides more effective and durable anti-cancer effects,” Sheng added.

The researchers were able to transform cold triple-negative breast cancer tumors into hot tumors by combining lacidipine, a long-acting antihypertensive drug, with chemotherapy. Lacidipine enhances the antitumor effect of chemotherapeutics by blocking tryptophan metabolism — preventing tumors from converting it into kynurenine. 

Lacidipine inhibits breast tumor growth in mice

To test the anticancer effects of lacidipine, the researchers gave mice with breast cancer lacidipine alone or in combination with either doxorubicin (DOX) or cisplatin chemotherapy drugs. They monitored tumor growth by imaging the tumor and measuring its size every few days for nearly a month.  

Among the nine groups of mice treated with different drug combinations, the researchers found that the group that received lacidipine and either DOX or cisplatin experienced the slowest tumor growth. This combination was more effective than combining a synthetic analog of tryptophan with DOX/cisplatin or DOX/cisplatin alone.

“Although lacidipine alone can inhibit tumor growth, it exhibits partial resistance to treatment, with refractory tumor growth observed between days 16 and 25,” Sheng mentioned.

“The combination of lacidipine with DOX or cisplatin did not result in refractory tumor growth during this period, and the drugs were able to sustain effective tumor inhibition,” she added, highlighting the importance of combining lacidipine with a chemotherapy drug. 

The researchers also found that treating the mice with lacidipine alone had no weight-loss or toxic effects, demonstrating its safe use. Wang believes it’s also possible that lacidipine could help lower the toxicity of chemotherapy drugs.

“There is some evidence suggesting that calcium channel blockers like lacidipine may reduce the toxicity of chemotherapy agents, either by protecting normal cells from damage or by altering drug uptake,” Wang said. “However, the specific effects of lacidipine in combination with DOX or cisplatin would need to be studied further in clinical trials to confirm whether it can reduce chemotherapy-induced side effects.”

Before clinical trials, Wang says that lacidipine should be tested on breast cancer organoids — 3D models that mimic the composition of breast tumors — and animal models of breast cancer with hypertension. Testing the drug in models of other cancer types will also help broaden its potential clinical applications and solidify its role as an anticancer agent, he added.

Wang also pointed out that some cancer treatments, including chemotherapy drugs, raise blood pressure, reinforcing the case for combined treatment with antihypertensives.

“Lacidipine may effectively manage this side effect, preventing high blood pressure from further impacting treatment outcomes or causing additional cardiovascular problems,” he said.

Reference: Fei Wang, et al. Calcium Channel Blocker Lacidipine Promotes Antitumor Immunity by Reprogramming Tryptophan Metabolism. Advanced Science (2024). DOI: 10.1002/advs.202409310

Feature image credit: National Cancer Institute on Unsplash