Synergistic Antitumor Activities of Sepantronium Bromide (YM155), a Survivin Suppressant, in Combination with Microtubule-Targeting Agents in Triple-Negative Breast Cancer Cells

Abstract

Triple-negative breast cancer (TNBC) has a poor prognosis compared to other subtypes, and effective treatment options are limited to cytotoxic agents, including microtubule-targeting agents, due to the lack of molecular targets. Here, we examined the combined effect of sepantronium bromide (YM155) and microtubule-targeting agents in TNBC models. The combination of YM155 with docetaxel showed synergistic antiproliferative and caspase 3/7-inducing effects in MRK-nu-1 and MDA-MB-453 human TNBC cell lines in vitro. YM155 also synergistically enhanced the efficacies of other microtubule-targeting agents, including paclitaxel and vinorelbine, which induced accumulation of survivin at the G2/M phase, whereas it did not affect the efficacy of doxorubicin. Combination treatment with YM155 and microtubule-targeting agents decreased the accumulation of survivin at the G2/M phase and induced greater apoptosis than either single agent alone. Further, combination treatment with YM155 and docetaxel also had a synergistic antitumor effect, achieving complete regression without exacerbation of body weight loss in all mice, in a MRK-nu-1 human TNBC xenograft model. These results suggest that survivin inhibition synergistically sensitize human TNBC cells to microtubule-targeting agents. Key words survivin; YM155; microtubule-targeting agent; triple-negative breast cancerBreast cancer is the second leading cause of cancer death among women in the United States.1) Triple-negative breast cancer (TNBC) is a clinical phenotype characterized by a lack of estrogen receptor (ER) and progesterone receptor (PR) expression as well as an absence of human epidermal growth factor-2 (HER-2) overexpression. Retrospective studies show that TNBC represents approximately 15% of total breast cancers and suggest that this cancer type is aggressive, with rapid tumor growth, a high incidence of metastasis, an increased possibility of distant recurrence, and a higher mortality rate than other breast cancers.2-4) Unlike patients with an ER/ PR-positive or HER-2-overexpressing subtype, this lack of molecular targets limits systemic treatment options for patients with TNBC to cytotoxic chemotherapy. Among them, microtubule-targeting agents, such as taxanes and vinca alkaloids are one of the most common class of chemotherapeutic drugs for the treatment of TNBC. 5,6) Despite the sensitivity of TNBC to chemotherapy, however, prognosis remains poor. The median time to death was shorter in patients with TNBC than in those with other subtypes. 7) Moreover, patients with TNBC who had residual disease after neoadjuvant chemotherapy had a particularly poor outcome.8) This poor prognosis and lack of therapeutic agents has underscored the demand for novel therapeutic options and strategies.Survivin, a member of the inhibitor of apoptosis (IAP) family of proteins, has been implicated in both cell survival and regulation of mitosis. 9) Overexpression of survivin is observed in various types of cancer, including breast cancer.10,11) Inhibition of survivin using ribozyme ...

Association of survivin splice variants with prognosis and treatment of breast cancer

“…In previous studies, it was demonstrated that tumor regression induced by YM155 in combination with docetaxel was accompanied by a decrease in intratumoral survivin and an increase in apoptosis rate. These results support the conclusion that survivin inhibition might be an effective way to enhance the efficacies of microtubule-targeting agents against TNBC [56] .…”

Dual induction of apoptotic and autophagic cell death by targeting survivin in head neck squamous cell carcinoma

“…Based on above, we predicate that survivin inhibitor may have synergic effects with traditional chemoreagents, such as platiums and taxanes, in HNSCC, which have been proven by previous studies and preclinical researches in various cancers. 15 , 40 , 41 , 42 Therefore, we examined the synergistic effects of YM155 combined with docetaxel in HNSCC using xenograft models. Results showed that YM155 combined with docetaxel exhibited better antitumor effects than either chemoreagent alone without additional toxicity, showing synergistic effects on HNSCC.…”

Phase II, multicenter, open-label, randomized study of YM155 plus docetaxel as first-line treatment in patients with HER2-negative metastatic breast cancer

“…In vitro studies demonstrated that inhibition of apoptosis by survivin required interaction with microtubules [ 18 ], providing a powerful rationale for the study of survivin together with anti-microtubule agents such as taxanes. YM155 in combination with the microtubule-targeted agent docetaxel induced greater apoptosis compared with either agent alone, resulting in complete tumor regression in a mouse TNBC xenograft model [ 19 ]. The results of a phase I study indicated that YM155 was well tolerated with manageable toxicities in patients with advanced solid tumors, including breast cancer, that were refractory to standard therapy [ 20 ].…”