Antiparasitic mebendazole (MBZ) effectively overcomes cisplatin resistance in human ovarian cancer cells by inhibiting multiple cancer-associated signaling pathways

Abstract

Ovarian cancer is the third most common cancer and the second most common cause of gynecologic cancer death in women. Its routine clinical management includes surgical resection and systemic therapy with chemotherapeutics. While the first-line systemic therapy requires the combined use of platinum-based agents and paclitaxel, many ovarian cancer patients have recurrence and eventually succumb to chemoresistance. Thus, it is imperative to develop new strategies to overcome recurrence and chemoresistance of ovarian cancer. Repurposing previously-approved drugs is a cost-effective strategy for cancer drug discovery. The antiparasitic drug mebendazole (MBZ) is one of the most promising drugs with repurposing potential. Here, we investigate whether MBZ can overcome cisplatin resistance and sensitize chemoresistant ovarian cancer cells to cisplatin. We first established and characterized two stable and robust cisplatin-resistant (CR) human ovarian cancer lines and demonstrated that MBZ markedly inhibited cell proliferation, suppressed cell wounding healing/migration, and induced apoptosis in both parental and CR cells at low micromole range. Mechanistically, MBZ was revealed to inhibit multiple cancer-related signal pathways including ELK/SRF, NFKB, MYC/MAX, and E2F/DP1 in cisplatin-resistant ovarian cancer cells. We further showed that MBZ synergized with cisplatin to suppress cell proliferation, induce cell apoptosis, and blunt tumor growth in xenograft tumor model of human cisplatin-resistant ovarian cancer cells. Collectively, our findings suggest that MBZ may be repurposed as a synergistic sensitizer of cisplatin in treating chemoresistant human ovarian cancer, which warrants further clinical studies.

Targeting the Unwindosome by Mebendazole Is a Vulnerability of Chemoresistant Hepatoblastoma

“…Moreover, this might have important clinical implications as it implies that one could use mebendazole together with cisplatin as combination regimen to substitute for cisplatin and doxorubicin treatments [ 8 ] in order to reduce toxic side effects of doxorubicin. In line with our results, a first study has recently demonstrated that mebendazole could overcome cisplatin resistance in ovarian cancer in vitro [ 61 ].…”

Carboxymethyl chitosan prolongs adenovirus‐mediated expression of IL‐10 and ameliorates hepatic fibrosis in a mouse model

“…All recombinant adenoviruses were constructed by using the AdEasy technology 24 . The Ad‐FLuc, which co‐expresses firefly luciferase (FLuc) and GFP, was generated as described in our previous studies 25–27 . For the construction of Ad‐IL10, the coding region of human IL‐10 was PCR amplified and subcloned into an adenoviral shuttle vector, pAdTrack‐CMV.…”

“… 24 The Ad‐FLuc, which co‐expresses firefly luciferase (FLuc) and GFP, was generated as described in our previous studies. 25 , 26 , 27 For the construction of Ad‐IL10, the coding region of human IL‐10 was PCR amplified and subcloned into an adenoviral shuttle vector, pAdTrack‐CMV. The resultant vector was used to generate the recombinant adenoviral plasmid pAd‐IL10 through homologous recombination with an adenoviral backbone vector in bacterial BJ5183 cells.…”

Cisplatin for cancer therapy and overcoming chemoresistance

“…Mebendazole (MBZ) is a multi-purpose anti-parasitic drug that reduces cisplatin resistance in OC and inhibit tumour proliferation, wound healing, cell migration and apoptosis by activating multiple signalling pathways. They consist of a member of the Ets (E twenty-six) oncogene family of transcription factors/dimer of serum response factor (ELK/SRF), Nuclear factor kappa beta – myelocytomatosis - viral oncogene homolog (NF-kB/MYC/MAX), and E2F/DP1) associated with human ovarian cancer [ 161 ]. Oleuropein, a phenolic ingredient, upregulated the expression of p21, p53, TNF Receptor Superfamily Member 10b (TNFRSF10B), miR-34a, miR-125b and miR-16 with the suppression of Bcl-2 and myeloid cell leukemia protein-1 (Mcl-1).…”