The gallium complex KP46 sensitizes resistant leukemia cells and overcomes Bcl-2-induced multidrug resistance in lymphoma cells via upregulation of Harakiri and downregulation of XIAP in vitro

Abstract

Tris-(8-quinolinolato)gallium(III) (KP46, AP-002) is an orally administered investigational anticancer and bone-protective drug currently being evaluated in patients with advanced solid tumors with bone involvement. Despite the clinical efficacy of other gallium compounds in non-Hodgkin’s lymphoma, effects of KP46 in hematological tumor settings have not been studied systematically before. We report here intriguing activities in various human cell lines, including such with multidrug resistance (MDR): In Nalm-6 lymphoblastic leukemia cell sublines, KP46 was capable of overcoming P-gp-related as well as P-gp-unrelated MDR. Apoptosis induction by KP46 was unaffected by bcl2-mediated vincristine-induced MDR in a BJAB lymphoma cell subline and even enhanced in a K562 leukemia subline with daunorubicin-induced MDR, which could be re-sensitized to daunorubicin by KP46. As the latter resistance is associated with lowered Harakiri (HRK) protein levels, a modulating effect of KP46 on HRK expression is suggested. This is consistent with the significant high upregulation of HRK on RNA and protein levels observed in KP46-treated parental BJAB cells according to qPCR and Western blot analysis, respectively. Furthermore, KP46 significantly reduces the protein level of X-linked inhibitor of apoptosis (XIAP) in BJAB cells, the most potent known inhibitor of apoptosis. Overall, these results indicate both a higher potential of HRK and XIAP as cellular targets for cancer therapy and a broader therapeutic potential of KP46 than hitherto envisaged.