Livestock Antibiotic Shows Promise in Ovarian Cancer in Preclinical Study

January 19, 2016

Article

A recent preclinical study conducted by researchers at the The University of Chicago Medical Center suggests that the antibiotic monensin may be effective in combating such a malignancy.

¹conducted by researchers at the The University of Chicago Medical Center suggests that the antibiotic monensin may be effective in combating ovarian cancer.

Monensin, commonly associated with veterinary use in beef cattle, chickens, and turkeys, shows capabilities of suppressing cancer-related pathways such as Elk1/SRF, AP1, NFκB and STAT, inhibiting cell proliferation, migration, and cell cycle progression, inducing apoptosis of human ovarian cancer cells, and reducing EGFR expression. On the contrary, the study, published in the December 2015 issue ofNature,also states monensin does not inhibit IGF-1R expression.

Researchers employed common human ovarian cancer lines, HeyA8 and SKOV3, to demonstrate the efficacy of monensin.

"Subconfluent HeyA8 and SKOV3 cells were grown in increasing concentrations of monensin. Crystal violet staining results indicated that monensin effectively inhibited cell proliferation in both cell lines at concentrations as low as 1 μM, and completely inhibited cell proliferation at 10 μM, especially in HeyA8 cells," said lead authors Youlin Deng, MD, and Junhui Zhang, MD, PhD, both of The University of Chicago Medical Center in the study.

The study further states that these results were confirmed by a quantitative analysis of the staining data (P  < .001), as well as a direct cell count after both the HeyA8 and SKOV3 cells were treated with various dosages of monensin. The study showed post-cell count that both the populations of HeyA8 and SKOV3 cells reacted to increasing doses of monensin.

Data from the study shows the width of the wound defect in HeyA8 cells when dosed 2 μM monensin was 75% and 68% at 24 hours and 36 hours, respectively, compared with 32% and 11%, respectively, at 24 hours and 36 hours without a dosage of monensin. With 4 μM monensin, roughly 80% of the wound defect remained open in both the HeyA8 and SKOV3 cells, suggesting monensin inhibits cell migration and cell wound healing.

"We found that the number of viable cells decreased significantly when the concentration of monensin increased in both cell lines at both examined time points. Further evaluation of antiproliferative effects was accomplished with the more sensitive and quantitative WST-1 proliferation assay, which found that statistically significant inhibition of cell proliferation occurred at concentrations as low as 0.25 μM monensin in HeyA8 and SKOV3," stated the authors.

The study also looked at monensin's ability to inhibit the Wnt/β-catenin activity. To achieve these results, researchers utilized exogenous Wnt3A to activate the Wnt pathway and then employed monensin on β-catenin signaling activity via nuclear staining. These results, while initially achieved in a colorectal cancer cell line in previous studies, exhibited similar results in ovarian cancer.

Through the last leg of the study, researchers examined thein vivoanticancer activity in xenograft tumor models of human ovarian cancers. According to the study, exponentially growing firefly luciferase-tagged HeyA8 ovarian cancer cells were injected subcutaneously into flanks of athymic nude mice.

After 3 days, the animals were given two doses of monensin at 8mg/kg and 16/mg/kg. The status of the ovarian cancer cells were monitored for up to 20 days, which showed monensin inhibited the growth of the ovarian cancer cells at both 15 and 20 days. Tumors retrieved from both a control group and the group receiving monensin showed the former having “significantly larger” tumors, higher bulk volume, and a more dense average tumor volume.

According to the study, monensin has been used in previous studies as a conjugate or liposome to deliver monoclonal antibodies, immunotoxins, or chemotherapy drugs to various cancer tumors. These studies have also concluded that the antibiotic may target cancer cells through a variety of techniques. In studies looking at prostate cancer, monensin decreased levels of CDK6, cyclin D1 and cyclin A, inhibited androgen, and induced oxidative stress in those cancer cells.

"In summary, we investigated the potential of repurposing monensin as an anticancer agent for human ovarian cancer. Our results revealed that monensin effectively inhibits cell proliferation, cell migration, and cell cycle progression, and induces apoptosis of human ovarian cancer cells. Monensin was shown to target multiple cancer-related signaling pathways such as Elk1/SRF, AP1, NFκB and STAT, and suppresses EGFR expression in ovarian cancer cells," said the authors in the study.

"Monensin was further shown to act synergistically with EGFR inhibitors and the chemotherapeutic drug oxaliplatin to inhibit cell proliferation and induce apoptosis of human ovarian cancer cells. Thein vivoxenograft studies further confirm that monensin effectively inhibits xenograft tumor growth by inhibiting cell proliferation through targeting EGFR signaling. Thus, our results strongly suggest that monensin may be repurposed as an antiovarian cancer agent."

The authors close the study by stating that further studies into the efficacy of monensin in ovarian cancer should be undertaken in both the preclinical and clinical setting.

References

Deng, Y. et al. Antibiotic monensin synergizes with EGFR inhibitors and oxaliplatin to suppress the proliferation of human ovarian cancer cells. Sci. Rep. 5, 17523; doi: 10.1038/srep17523 (2015).