Pharmacological Modulation of Proton Channel Hv1 in Cancer Therapy: Future Perspectives

Abstract

The pharmacological modulation of the immunosuppressive tumor microenvironment has emerged as a relevant component for cancer therapy. Several approaches aiming to deplete innate and adaptive suppressive populations, to circumvent the impairment in antigen presentation, and to ultimately increase the frequency of activated tumor-specific T cells are currently being explored. In this review, we address the potentiality of targeting the voltage-gated proton channel, Hv1, as a novel strategy to modulate the tumor microenvironment. The function of Hv1 in immune cells such as macrophages, neutrophils, dendritic cells, and T cells has been associated with the maintenance of NADPH oxidase activity and the generation of reactive oxygen species, which are required for the host defense against pathogens. We discuss evidence suggesting that the Hv1 proton channel could also be important for the function of these cells within the tumor microenvironment. Furthermore, as summarized here, tumor cells express Hv1 as a primary mechanism to extrude the increased amount of protons generated metabolically, thus maintaining physiologic values for the intracellular pH. Therefore, because this channel might be relevant for both tumor cells and immune cells supporting tumor growth, the pharmacological inhibition of Hv1 could be an innovative approach for cancer therapy. With that focus, we analyzed the available compounds that inhibit Hv1, highlighted the need to develop better drugs suitable for patients, and commented on the future perspectives of targeting Hv1 in the context of cancer therapy.

Functions and Mechanisms of the Voltage-Gated Proton Channel Hv1 in Brain and Spinal Cord Injury

“…It is worth reiterating that Hv1 expression is not exclusive to phagocytes of myeloid lineage, as some groups have reported expression in B and T lymphocytes (Fernandez et al, 2016). In B cells, Hv1 has been shown to regulate the strength of BCR signaling (Capasso et al, 2010).…”

“…Several proton current inhibitors, such as 4-aminopyridine, amantadine, amiloride, D600, nicardipine, imipramine, DM, chlorpromazine, clozapine, haloperidol, and rimantadine have potentially indirect effects on Hv1 function, presumably by increasing intracellular pH (Shin et al, 2015). In particular, epigallocatechin-3-gallate might interfere with Hv1 channel activity by modifying the lipid bilayer structure (Seredenina et al, 2015;Fernandez et al, 2016). Additionally, a toxic peptide C6 was identified as a high potential Hv1 blocker with specificity and high affinity (Kd = 1 nM) (Tang et al, 2020).…”

Scorpion Venom: Detriments and Benefits

“…Furthermore, AGAP showed strong anticancer effects, including the inhibition of stemness, epithelial-mesenchymal transition, migration, and invasion toward MCF-7 and MDA-MB-231 breast cancer cells [228]. It also inhibited the voltage-gated proton channel Hv1 [229], which has been investigated as a possible target for cancer therapy and has been extensively reviewed elsewhere [230]. Two studies on a third M. martensii peptide, BmKn2, indicated that this peptide could selectively induce apoptosis in cancerous human oral cells, while normal cells were affected to a much lesser extent [231,232].…”

Scorpion toxin inhibits the voltage‐gated proton channel using a Zn2+‐like long‐range conformational coupling mechanism

“…Furthermore, several studies suggested H V 1 channel might play a role in cancer, being involved in proliferation and metastasis of tumour cells (Wang et al, ; Wang, Li, Wu, Che, & Li, ; Wang, Wu, Li, Zhang, & Li, ; Wang, Zhang, & Li, ). It was proposed that blocking the H V 1 channel could be a promising approach in cancer therapy by modulating the immunosuppressive tumour micro‐environment and inducing tumour cell acidification (Fernandez, Pupo, Mena‐Ulecia, & Gonzalez, ). An earlier study showed that H V 1 channel inhibition promoted apoptosis of leukaemic Jurkat cells (Asuaje et al, ).…”