Quinacrine sensitizes hepatocellular carcinoma cells to TRAIL and chemotherapeutic agents

Abstract

Quinacrine has been widely explored in treatment of malaria, giardiasis, and rheumatic diseases. We find that quinacrine stabilizes p53 and induces p53-dependent and independent cell death. Treatment by quinacrine alone at concentrations of 10-20 mM for 1-2 d cannot kill hepatocellular carcinoma cells, such as HepG2, Hep3B, Huh7, which are also resistant to TRAIL. However, quinacrine renders these cells sensitive to treatment by TRAIL. Co-treatment of these cells with quinacrine and TRAIL induces overwhelming cell death within 3-4 h. Levels of DR5, a pro-apoptotic death receptor of TRAIL, are increased upon treatment with quinacrine, while levels of Mcl-1, an anti-apoptotic member of the Bcl-2 family, are decreased. While the synergistic effect of quinacrine with TRAIL appears to be in part independent of p53, knockdown of p53 in HepG2 cells by siRNA results in more cell death after treatment by quinacrine and TRAIL. The mechanism by which quinacrine sensitizes hepatocellular carcinoma cells to TRAIL and chemotherapies, and the potential for clinical application currently are being further explored. Lastly, quinacrine synergizes with chemotherapeutics, such as adriamycin, 5-FU, etoposide, CPT11, sorafenib, and gemcitabine, in killing hepatocellular carcinoma cells in vitro and the drug enhances the activity of sorafenib to delay tumor growth in vivo.

Quinacrine induces apoptosis in human leukemia K562 cells via p38 MAPK-elicited BCL2 down-regulation and suppression of ERK/c-Jun-mediated BCL2L1 expression

“…Moreover, quinacrine-induced NFκB inactivation promotes TRAIL, oxaliplatin and 5-fluorouracil cytotoxicity in human colon carcinoma cell lines via growth inhibition (Jani et al, 2010;Gallant et al, 2011). Consistently, quinacrine is a chemosensitizer that can enhance chemotherapeutic drug-induced apoptosis of cancer cells (Friedman et al, 2007;Wang et al, 2010Wang et al, , 2011Wu et al, 2012). Noticeably, quinacrine-induced chemosensitization is primarily attributed to altered BCL2 family protein expression (Jani et al, 2010;Wang et al, 2010Wang et al, , 2011Gallant et al, 2011).…”

Quinacrine synergizes with 5-fluorouracil and other therapies in colorectal cancer

“…9 We thereafter determined that quinacrine could sensitize hepatocellular carcinoma to TRAIL through the induction of DR5. 10 We also showed that quinacrine, in combination with sorafenib, could synergize to significantly diminish levels of Mcl-1 protein, an anti-apoptotic Bcl-2 family member that is essential for tumor survival in many types of human tumors. 11 Together, these data supported further exploration of quinacrine as an anticancer agent.…”

“…We have shown that quinacrine can overcome the resistance of hepatocellular carcinoma cells to TRAIL and a wide array of chemotherapies. 10 It has also been shown that quinacrine can synergize with chemotherapy in a variety of other systems. 26,27 Given its broad spectrum of activity, we thus hypothesized that quinacrine could enhance, if not synergize, with both conventional chemotherapeutic agents and targeted therapies in colorectal cancer.…”

Targeting TRAIL Death Receptor 4 with Trivalent DR4 Atrimer Complexes

“…It should be noted that sensitivity of cancer cells to TRAIL-mediated apoptosis is determined by multiple factors and that resistance mechanisms often involve intracellular regulators of apoptosis such as Mcl-1 or cFLIP. Our lab and others have reported on synergistic combinations of TRAIL and chemotherapy or targeted agents to overcome such resistance mechanisms (21)(22)(23). Such combinations should be explored with DR4 Atrimer complexes to overcome potential resistance mechanisms and expand their activity profile.…”