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. 2020 Dec:92:102307.
doi: 10.1016/j.ceca.2020.102307. Epub 2020 Oct 14.

Inhibition of TRPM7 with waixenicin A reduces glioblastoma cellular functions

Raymond Wong  1 , Haifan Gong  1 , Rahmah Alanazi  1 , Andrew Bondoc  2 , Amanda Luck  2 , Nesrin Sabha  3 , F David Horgen  4 , Andrea Fleig  5 , James T Rutka  6 , Zhong-Ping Feng  7 , Hong-Shuo Sun  8
Affiliations

Inhibition of TRPM7 with waixenicin A reduces glioblastoma cellular functions

Raymond Wong et al. Cell Calcium. 2020 Dec.

Abstract

Glioblastoma (GBM) is the most common malignant primary brain tumour originating in the CNS. Median patient survival is <15 months with standard treatment which consists of surgery alongside radiation therapy and temozolomide chemotherapy. However, because of the aggressive nature of GBM, and the significant toxicity of these adjuvant therapies, long-term therapeutic effects are unsatisfactory. Thus, there is urgency to identify new drug targets for GBM. Recent evidence shows that the transient receptor potential melastatin 7 (TRPM7) cation channel is aberrantly upregulated in GBM and its inhibition leads to reduction of GBM cellular functions. This suggests that TRPM7 may be a potential drug target for GBM treatment. In this study, we assessed the effects of the specific TRPM7 antagonist waixenicin A on human GBM cell lines U87 or U251 both in vitro and in vivo. First, we demonstrated in vitro that application of waixenicin A reduced TRPM7 protein expression and inhibited the TRPM7-like currents in GBM cells. We also observed reduction of GBM cell viability, migration, and invasion. Using an intracranial xenograft GBM mouse model, we showed that with treatment of waixenicin A, there was increased cleaved caspase 3 activity, alongside reduction in Ki-67, cofilin, and Akt activity in vivo. Together, these data demonstrate higher GBM cell apoptosis, and lower proliferation, migration, invasion and survivability following treatment with waixenicin A.

Keywords: TRPM7; drug target; glioblastoma; ion channels; waixenicin A.

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