Urease-induced alkalinization of extracellular pH and Its antitumor activity in human breast and lung cancers
Wah Yau Wong, Carl I. Deluca, Baomin Tian, Iain Wilson, Sharon Molund, Nalini Warriar, Manjapra V. Govindan, Donald Segal and Heman Chao
Jack bean urease catalyzes the decomposition of urea into ammonia, which in turn increases the pH of the surrounding medium. Based on these two properties, we have investigated the antitumor effects of urease in vitro and in vivo on human lung and breast cancer cell lines either by the enzyme itself or in combination with other chemotherapeutic drugs. First, through the generation of toxic ammonia, urease exerted direct cytotoxicity on A549 and MDA-MB-231 tumor cells with LC50 of 0.22 and 0.45 U/ml, respectively. Them cytotoxic effects could effectively be blocked using the reversible urease inhibitor acetohydroxamic acid. Complete protection was observed at dose >2 mM. In addition, nude mouse xenograft models demonstrated that intratumoral urease injections (1 – 10 U/dose) inhibited A549 and MCF-7 tumor growth in vivo. Second, when combined with weak-base anticancer drugs, urease provided indirect antitumor effects via pH augmentation. Alkalinization of extracellular pH by urease (2 U/ml) and urea (> 2 mM) was found to enhance the antitumor efficacy of doxorubicin (50 mM) and vinblastine (100 mM) significantly.