Chloroquine and its analogs: A new promise of an old drug for effective and safe cancer therapies

Abstract

Chloroquine (CQ), N′-(7-chloroquinolin-4-yl)-N,N-diethyl-pentane-1,4-diamine, is widely used as an effective and safe anti-malarial and anti-rheumatoid agent. CQ was discovered 1934 as “Resochin” by Andersag and co-workers at the Bayer laboratories. Ironically, CQ was initially ignored for a decade because it was considered too toxic to use in humans. CQ was “re-discovered” during World War II in the United States in the course of anti-malarial drug development. The US government-sponsored clinical trials during this period showed unequivocally that CQ has a significant therapeutic value as an anti-malarial drug. Consequently, CQ was introduced into clinical practice in 1947 for the prophylaxis treatment of malaria (Plasmodium vivax, ovale and malariae). CQ still remains the drug of choice for malaria chemotherapy because it is highly effective and well tolerated by humans. In addition, CQ is widely used as an anti-inflammatory agent for the treatment of rheumatoid arthritis, lupus erythematosus and amoebic hepatitis. More recently, CQ has been studied for its potential as an enhancing agent in cancer therapies. Accumulating lines of evidence now suggest that CQ can effectively sensitize cell-killing effects by ionizing radiation and chemotherapeutic agents in a cancer-specific manner. The lysosomotrophic property of CQ appears to be important for the increase in efficacy and specificity. Although more studies are needed, CQ may be one of the most effective and safe sensitizers for cancer therapies. Taken together, it appears that the efficacy of conventional cancer therapies can be dramatically enhanced if used in combination with CQ and its analogs.

Introduction

If we want to further improve cancer cure rates, we need to understand the detailed control mechanism how anti-cancer therapeutics function in the context of cellular and molecular control pathways in normal and cancer cells. Furthermore, the limitation of drug concentrations used for therapy is a serious problem, mainly due to side effects. Thus, there is an urgent need for developing more effective cancer modalities with minimal side effects. Since cancer is caused by a complex chain of events, combinational modalities may provide a better response to cancer therapy (Cheng et al., 2008, Rosales-Hernandez et al., 2009).

A study of 68 newly approved drugs estimated that developing a single effective cancer drug takes an average of 15 years and US$800 million (DiMasi et al., 2003). One approach to overcome this enormous problem may be developing a new use of existing drugs. The renowned pharmacologist and Nobel laureate James Black said, “the most fruitful basis for the discovery of a new drug is to start with an old drug” (Chong and Sullivan, 2007). Since many existing drugs have been studied for their pharmacokinetics and safety profiles, and often have already been approved by regulatory agencies for human use, any newly identified use of them can be rapidly evaluated in phase II trials (DiMasi et al., 2003). Developing a known drug for another clinical purpose is termed “repurposing”. The efficacy and specificity of a known drug can also be improved by modifications of its chemical side chains and functional groups, which is termed “repositioning”.

Chloroquine is a well-known 4-aminoquinoline class of drug that is widely used for the prophylaxis treatment of malaria (Wiesner et al., 2003). Even after six decades of use, CQ still remains the drug of choice for malaria treatment because it is effective, low toxic to humans, and inexpensive (Breckenridge and Winstanley, 1997). Biochemical data suggest that this class of compounds enter acidic vacuoles of host cells, where they inhibit the growth of parasites by forming a complex with haematin (Dorn et al., 1995, Pandey et al., 2001, Sullivan et al., 1996). The anti-inflammatory property of CQ also makes it a useful agent for the treatment of rheumatoid arthritis (Augustijns et al., 1992, Titus, 1989), lupus erythematosus (Meinao et al., 1996) and amoebic hepatitis (Conan, 1948). Furthermore, CQ inhibits pro-inflammatory cytokine release into the blood stream, suggesting that it may have therapeutic benefits for chronic inflammation diseases as well as for relieving symptoms caused by bacteria-induced inflammation (Karres et al., 1998). Chloroquine is currently in clinical trials as an investigational anti-retroviral agent in humans with HIV-1/AIDS (Savarino et al., 2003, Savarino et al., 2006) and as a potential anti-viral agent against chikungunya fever (Savarino et al., 2007). In addition, CQ has been studied for its potential in the enhancement of radiation therapy (Beierwaltes et al., 1968, Zhao et al., 2005), chemotherapy, and combinational therapy for cancer ( Carew et al., 2006, Degtyarev et al., 2008, Hagihara et al., 2000, Hu et al., 2008). Our current review focuses on CQ and its analogs as enhancement agents for cancer therapies.