HONG KONG – The common anti-parasitic agent, ivermectin, may be a viable new option to treat breast cancer, reported Chinese researchers, who have demonstrated that it inhibited the proliferation of breast cancer cells and elucidated its mechanism of action in a new study.

According to the Thomson Reuters Incidence & Prevalence Database, breast cancer is the most common cancer among women worldwide, accounting for 25 percent of cases. In 2012, 1.68 million breast cancers were reported globally, resulting in 522,000 deaths.

Survival rates in developed countries are relatively high. In the U.S., for example, the National Cancer Institute estimates up that to 90 percent of treated patients survive after five years, depending on cancer type, extent of the disease and the patient's age. Survival rates in developing countries are generally poorer, with successful treatment of breast cancer remaining a clinical challenge.

"Over recent decades, there have been a spate of new therapies for treating breast cancer, due to an increased understanding of the biology and genetics of breast cancer, with drugs having been developed to target the cancer based on its different biological pathways," said Ava Kwong, clinical associate professor and chief of the Breast Surgery Division, Department of Surgery, Li Ka Shing faculty of Medicine, the University of Hong Kong, Queen Mary Hospital.

"The challenge, however, is that the cancers are 'intelligent' and targeting one pathway may prompt them to grow using alternative pathways, with the best combinations of treatments having yet to be discovered. Moreover, even with early diagnosis, there remains a percentage of cancers that are genetically and biologically aggressive, despite their early discovery," Kwong told BioWorld Asia.

"There is therefore an urgent need not only for more effective breast cancer treatments, but also the best combination of treatments, and for biomarkers for early detection of cancer and recurrences so we can treat them earlier," she said.

"Moreover, there is an urgent need to find biomarkers to detect cancers in a premalignant stage and even methods leading to the prevention of the cancer using drugs, which ideally would have minimal or acceptable side effects."

WORMS

A broad-spectrum antiparasitic agent used against worm infestations, ivermectin is mainly used to treat onchocerciasis, or river blindness. Relatively inexpensive to manufacture, it is also effective against other worm infections, and is included on the WHO's List of Essential Medicines for those indications.

Several years ago, however, Russian researchers reported that ivermectin almost completely suppressed the growth of human melanoma and several other cancer xenografts in mice, without any apparent adverse effects, although the molecular mechanism underlying this anticancer effect was poorly understood.

For the present study, "we screened a large number of chemical compounds and found that ivermectin could markedly decrease cell viability of cancer cells in a dose-dependent manner, particularly in breast cancer," said study leader Canhua Huang, a professor in the State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and the Collaborative Innovation Center for Biotherapy in Chengdu, China.

The mass screening also revealed other molecules shown to possess potent anticancer activity, including the antifungal, itraconazole (Sporanox, Johnson & Johnson), the anthelmintic, pyrvinium, and the flavonol, quercetin, a dietary supplement that is widely promoted for the treatment and prevention of cancer, noted Huang.

"In addition to breast cancer, we also examined the anticancer activity of ivermectin in other cancer cells, including colon, ovarian and lung cancer cells and in cervical carcinoma," he told BioWorld Asia. "We also showed in in vitro studies that ivermectin significantly suppressed cancer cell proliferation in HCT116, SKOV3, Hela and A549 cell lines," he added.

In the July 18, 2016, online Cancer Research, Huang and his team reported having found a role for ivermectin in breast cancer suppression through the activation of cytostatic autophagy, the cellular process allowing orderly degradation and recycling of cellular components, both in vitro and in vivo.

"In order to determine whether autophagy was involved in the anticancer effect of ivermectin, we blocked the activation of cytostatic autophagy in cancer cells in vitro using autophagy inhibitors or [small interfering] siRNA transfection before ivermectin treatment," explained Huang.

"Our data indicated that ivermectin inhibited breast cancer cell growth by regulating autophagy, with these intriguing preclinical results suggesting a mechanistic rationale for clinically evaluating ivermectin as a treatment option for breast cancer."

Mechanistically, ivermectin-induced autophagy in breast cancer cells was shown to be due to effects on P21-activated kinase 1 (PAK1) expression.

"PAK1 has been demonstrated to be increased in breast cancer and is known to play a key role in promoting tumor growth and drug resistance," said Huang, noting that the oncogenic function of PAK1 has also been observed in other cancers, such as colon and ovarian cancers, and in neurofibromatosis.

"Thus, further research studies targeting PAK1 may provide an optional therapeutic strategy for tumors with PAK1 overexpression. On the basis of our findings, the combination of traditional anticancer treatment with ivermectin seems to be a rational way to treat cancer cells with PAK1-involved drug resistance."

In addition, the inhibition of PAK1 was shown to decrease the phosphorylation level of Akt, resulting in blockade of the Akt/mTOR intracellular signaling pathway, which plays a central role in cell cycle regulation. In breast cancer xenografts, the ivermectin-induced cytostatic autophagy led to the suppression of tumor growth.

That is a significant finding, as "the Akt/mTOR signaling pathway is a major pathway accounting for autophagy activation. Besides regulation of the autophagic process, Akt/mTOR signaling has been demonstrated to be involved in diverse other biological processes, such as cell growth, metabolism and tumorigenesis," said Huang.

"Together, our results provide a molecular basis for the use of ivermectin to inhibit the proliferation of breast cancer cells and indicate that ivermectin is a potential option for the treatment of breast cancer," noted Huang.

"From our study data, we can observe that ivermectin treatment is capable of suppressing important regulators in the cell cycle, which resulted in cell cycle arrest. This suggests that further studies may need to be performed to investigate whether cell cycle arrest is involved in ivermectin-mediated cytostatic autophagy," he told BioWorld Asia.

Moreover, "our study findings provide insights into the [mechanisms underlying the] anticancer efficacy of ivermectin, which provides the preclinical rationale for the further exploration and broadening of the clinical evaluation of ivermectin for the treatment of breast cancer."