The proton pump inhibitor inhibits cell growth and induces apoptosis in human hepatoblastoma

Abstract

The V-ATPase inhibitor Baf-A1 has been proven to selectively inhibit the reproduction and induce the apoptosis of hepatoblastoma cells without adversely influencing normal hepatic cells. With these effects, V-ATPase inhibitors may hold promise as therapeutic agents for hepatoblastoma. Given that three V-ATPase-related genes (ATP6V0D2, ATP6V1B1, and ATP6V0A1) were more weakly expressed in the hepatoblastoma cells of the Baf-A1-treated group than in the Baf-A1-free cells, drug development targeting V-ATPase gene of hepatoblastomas is expected.

Mode of Cell Death Induction by Pharmacological Vacuolar H+-ATPase (V-ATPase) Inhibition

“…5S). Interestingly, all tested nontumor cells were significantly less sensitive toward V-ATPase inhibition by archazolid compared with SKBR3 breast carcinoma cells or a set of other tumor cells, an important fact also reported by Morimura et al for normal liver cells in contrast to hepatoblastoma cells (8).…”

“…It binds within the equatorial region of the V 0 rotor subunit c (6). There are reports on effects of V-ATPase inhibitors including archazolid on tumor growth and invasion (7)(8)(9); however, detailed investigations into the underlying molecular mechanism and signaling pathways are missing. In this respect archazolid could serve as a helpful pharmacological tool to decipher the role of V-ATPase in cell death * This work was supported by the Deutsche Forschungsgemeinschaft Grant FOR 2 The abbreviations used are: V-ATPase, vacuolar H ϩ ATPase; AMPK, AMPactivated protein kinase; ⌬m, mitochondrial potential; HIF1␣, hypoxiainducible factor-1␣; HMEC, human mammary endothelial cell; HUVEC, human umbilical vein endothelial cell; JC-1, 5,5Ј,6,6Ј-tetrachloro-1,1Ј,3,3Ј-tetraethylbenzimidazol-carbocyanine iodide; 3MA, 3-methyladenine; mTOR, mammalian target of rapamycin; NBDG, 2-[N- (7-…”

Vacuolar ATPase as a potential therapeutic target and mediator of treatment resistance in cancer

“…Importantly, chemical inhibition appears to show selectivity for cancer cells compared to normal cells. For example, baf‐A1 inhibition resulted in significant reductions in hepatoblastoma cell growth compared to normal human hepatocytes 71. One of the benzolactone enamides and a derivative of salicylihalamide was shown to have a significantly synergistic effect on the viability of NCI‐H1155 lung cancer cells when applied with paclitaxel increasing the sensitivity of the latter 1000‐fold 72, 73.…”

Estimating the rotation rate in the vacuolar proton-ATPase in native yeast vacuolar membranes

“…Specific inhibitors of V-ATPase are important because the enzyme is a potential therapeutic target in certain diseases, e.g., osteoporosis, deafness and cancer (Linnett and Beechey 1979;Farina and Gagliardi 1999;Bowman and Bowman 2005;Lu et al 2005;Morimura et al 2008;Otero-Rey et al 2008;Supino et al 2008;Hinton et al 2009;Perez-Sayans et al 2009;McHenry et al 2010;Nishisho et al 2011). The macrolide antibiotics concanamycin A and bafilomycin are the most potent and most selective inhibitors of V-ATPase, with IC 50 values down to the nM region (Bowman et al 1988;Farina and Gagliardi 1999;Gagliardi et al 1999;Huss et al 2002;Dixon et al 2008).…”