Effects of bafilomycin A1, a vacuolar type H⁺ATPase inhibitor, on the thermosensitivity of a human pancreatic cancer cell line

Abstract

The combination of these two drugs significantly lowered pHi and increased thermosensitivity of cancer cells in vitro and enhanced the heat-induced the growth delay of AsPC-1 tumours grown s.c in the legs of BALB/cA nude mice.

Manipulating extracellular tumour pH: an effective target for cancer therapy

“…Table 4 lists some inhibitors and their target proton pumps. 90,[94][95][96][97][98][99][100][101][102] As seen in Table 4, the current inhibitor drugs mainly focus on two major pH regulators (V-ATPase and SLC9A1) and only one of these drugs, cariporide, has been successfully developed to phase III clinical trial.…”

“…Interestingly, decreasing pH i may increase hyperthermia efficacy (over 42 C) and the programming cell death response to TNF (tumour necrosis factor) induced by apoptosis ligand, also known as TRAIL. 96,[103][104][105] For example, both balomycine A1 (an inhibitor of V-ATPase) and EIPA (an inhibitor of the Na + /H + exchanger) increased the thermo-sensitivity of the AsPC-1 tumours (grown in nude mice) by individually mildly decreasing pH i , and the thermo-sensitivity was markedly enhanced by the sharp decrease in pH i , resulting from the synergetic effect of the combination of these two therapies. 96 Fig .…”

“…96,[103][104][105] For example, both balomycine A1 (an inhibitor of V-ATPase) and EIPA (an inhibitor of the Na + /H + exchanger) increased the thermo-sensitivity of the AsPC-1 tumours (grown in nude mice) by individually mildly decreasing pH i , and the thermo-sensitivity was markedly enhanced by the sharp decrease in pH i , resulting from the synergetic effect of the combination of these two therapies. 96 Fig . 7 outlines the functions of some specic pH regulators and relatively main inhibitors for tumour cells.…”

Bisbenzimidazoles: Anticancer Vacuolar (H+)-ATPase Inhibitors

“…Despite the clear involvement of V-ATPases in cancer, to date, therapeutic use of V-ATPase targeting small molecules have not reached the clinic. Natural products macrolide antibiotics, such as bafilomycin and concanamycin, potently inhibit V-ATPases [33][34][35][36][37] (Figure 2), but their use is complicated by non-specific effects on other targets. Moreover, these molecules have been difficult to synthesize in large quantities.…”

Bafilomycin A1 and its attenuating effect on tumour growth in systemic malignancies, especially gastrointestinal malignancies

“…Bafilomycin A1 also decreases intracellular pH within the cancerous cells and thereby accentuates the thermosenstivity of the tumour. These effects are especially more pronounced when bafilomycin A1 is used in conjunction with EIPA [5-(N-ethyl-N-isopropyl)amiloride] therapy [6]. These effects have been seen both in vivo and in vitro.…”