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Aspirin Reverses Chemotherapy Resistance in Breast Cancer Cells and Mice

A team of scientists has discovered that the common pain medication aspirin can prevent breast cancer cells from resisting the effects of an approved chemotherapy drug, according to a new study published in the October 20 issue of Science Signaling.

The results reveal that aspirin can disable tiny molecular pumps that cancer stem cells — a type of cancer cell that drives the progression and spread of tumors — use to expel toxic drugs.

In experiments with mouse models of breast cancer, aspirin also boosted the killing power of doxorubicin, a common chemotherapy medication. Although the aspirin didn't show strong effects in isolation, mice that received both drugs had smaller tumors than mice that only received doxorubicin.

Although more work is needed to translate these findings to the clinic, the experiments add to a growing body of evidence suggesting that this safe and well-known medication could be repurposed as a supportive treatment for patients receiving chemotherapy.

The past several decades have witnessed enormous strides in the detection and treatment of different types of cancer. However, clinicians continue to struggle with the fact that many tumors frequently become resistant to chemotherapy drugs, which worsens patient outcomes and raises the chance of tumors relapsing.

In search of any weaknesses, researchers have recently focused some of their attention on cancer stem cells, which possess unique self-renewal properties similar to normal stem cells, according to the National Institutes of Health.

The field of cancer research has undergone a substantial paradigm shift as scientists have increasingly recognized these cells as critical cogs in the processes of tumor growth, resistance to chemotherapy, and suppression of the immune system, said Tanya Das, an emeritus scientist at the Bose Institute in Kolkata, India and senior author of the new study.

"Thus, sensitizing these highly resistant cancer stem cells to chemotherapy might be the only solution to us getting relapse-free cancer patients," she said.

Teams have previously tested drugs that selectively target cancer stem cells, but most of these compounds failed to advance through trials because of their high toxicity and potential for side effects. These obstacles had led some scientists to conclude that cancer stem cells may be "non-targetable" with existing drugs, according to the new study.

Aspirin can make cancer stem cells more sensitive to chemotherapy. | Bose Institute, IPGMER, BITS-Pilani

Apoorva Bhattacharya, a researcher at the Bose Institute and lead author of the new study, and colleagues therefore searched for an alternate, safer compound that can hone in on cancer stem cells without causing severe side effects.

After searching the literature, Bhattacharya's team decided to investigate aspirin, which has been researched as a potential cancer therapy since 1994. Since then,several studies have reported that doses of aspirin can interfere with the growth of glioblastoma, pancreatic cancer, and other malignancies.

First, the team used molecular techniques to study the expression of genes in invasive breast cancer cells. These experiments showed that cancer stem cells within the tumors harbored two molecules named Oct4 and Sox2. The two proteins suppressed a third protein named SMAR1, which normally keeps drug resistance in check by inhibiting molecular pumps that cancer cells use to expel drugs.

The researchers also studied data from 2,326 patients with various cancers. They saw that patients who showed a more active SMAR1 gene tended to have longer overall survival times than individuals with less activity in the gene. The gene was also less active in stage 3 breast cancer compared with stage 2 breast cancer, suggesting that SMAR1 fades in strength as the disease progresses.

The scientists then treated spheres of chemotherapy-resistant breast cancer cells with aspirin and observed that the drug substantially cut the amount of Oct4 and Sox2, restored levels of SMAR1, and left the cells more vulnerable to the killing effects of doxorubicin.

After these cell-based studies, the authors administered aspirin, doxorubicin, or both drugs to mice with breast cancer tumors. Although the aspirin didn't have a large impact on tumors alone, the mice that received both aspirin and doxorubicin showed larger drops in tumor size compared with animals that received either drug alone.

Das likened the effects of aspirin on the cells to a double-edged sword, as the treatment both counteracted drug resistance and directly interfered with the self-renewing properties of the cancer stem cells.

"Since aspirin is already an approved drug and is regularly used as an anti-inflammatory agent, having no systemic toxicity, it's a great choice for repurposing for anticancer therapy," said Das. She stressed that repurposing well-known agents like aspirin is less expensive and more convenient than discovering new drugs, making aspirin a prime target for future studies.

The research group recently published another paper showing that aspirin can also sensitize stem-like cells from non-small cell carcinoma — a common form of lung cancer — to chemotherapy drugs, raising the tantalizing possibility that the compound could prove useful for a range of malignancies. However, Das cautioned that more research is necessary to establish whether aspirin has the potential to treat other tumors.

The next step towards clinical implementation would involve a large randomized trial, said Das, and several clinical trials are already underway. Researchers are currently testing aspirin as a treatment for breast cancer, melanoma, and colorectal cancer, according to an online list maintained by the National Institutes of Health.

[Credit for associated image: Annie Cavanaugh | Wellcome Images]