Chloroquine in cancer therapy: a double-edged sword of autophagy.

Autophagy is a homeostatic cellular recycling system that is responsible for degrading damaged or unnecessary cellular organelles and proteins. Cancer cells are thought to use autophagy as a source of energy in the unfavorable metastatic environment, and a number of clinical trials are now revealing the promising role of chloroquine, an autophagy inhibitor, as a novel antitumor drug. On the other hand, however, the kidneys are highly vulnerable to chemotherapeutic agents. Recent studies have shown that autophagy plays a protective role against acute kidney injury, including cisplatin-induced kidney injury, and thus, we suspect that the use of chloroquine in combination with anticancer drugs may exacerbate kidney damage. Moreover, organs in which autophagy also plays a homeostatic role, such as the neurons, liver, hematopoietic stem cells, and heart, may be sensitive to the combined use of chloroquine and anticancer drugs. Here, we summarize the functions of autophagy in cancer and kidney injury, especially focusing on the use of chloroquine to treat cancer, and address the possible side effects in the combined use of chloroquine and anticancer drugs.

[1]  L. Cantley,et al.  Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation , 2009, Science.

[2]  John A Kellum,et al.  Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury , 2007, Critical care.

[3]  A. Cuervo,et al.  Lipophagy: Connecting Autophagy and Lipid Metabolism , 2012, International journal of cell biology.

[4]  Y. Isaka,et al.  The protective role of autophagy against aging and acute ischemic injury in kidney proximal tubular cells , 2011, Autophagy.

[5]  Masaaki Komatsu,et al.  Loss of autophagy in the central nervous system causes neurodegeneration in mice , 2006, Nature.

[6]  J. Verweij,et al.  Renal toxicities of chemotherapy. , 2006, Seminars in Oncology.

[7]  木村 友則.  Autophagy protects the proximal tubule from degeneration and acute ischemic injury , 2012 .

[8]  E. Soilleux,et al.  The autophagy protein Atg7 is essential for hematopoietic stem cell maintenance , 2011, The Journal of experimental medicine.

[9]  H. Nagawa,et al.  Chloroquine potentiates the anti-cancer effect of 5-fluorouracil on colon cancer cells , 2010, BMC Cancer.

[10]  S. Emr,et al.  Autophagy as a regulated pathway of cellular degradation. , 2000, Science.

[11]  D. Warhurst,et al.  Lysosomes, pH and the Anti-malarial Action of Chloroquine , 1972, Nature.

[12]  Masaaki Komatsu,et al.  Autophagy: Renovation of Cells and Tissues , 2011, Cell.

[13]  F. Di Virgilio,et al.  Autophagy-Dependent Anticancer Immune Responses Induced by Chemotherapeutic Agents in Mice , 2011, Science.

[14]  K. Ryan,et al.  The multiple roles of autophagy in cancer , 2011, Carcinogenesis.

[15]  Y. Eishi,et al.  Autophagy-deficient mice develop multiple liver tumors. , 2011, Genes & development.

[16]  Keiji Tanaka,et al.  Persistent activation of Nrf2 through p62 in hepatocellular carcinoma cells , 2011, The Journal of cell biology.

[17]  J. Sotelo,et al.  Adding Chloroquine to Conventional Treatment for Glioblastoma Multiforme , 2006, Annals of Internal Medicine.

[18]  C. Thompson,et al.  Therapeutic targets in cancer cell metabolism and autophagy , 2012, Nature Biotechnology.

[19]  Takeshi Tokuhisa,et al.  The role of autophagy during the early neonatal starvation period , 2004, Nature.

[20]  O. Kretz,et al.  Autophagy plays a critical role in kidney tubule maintenance, aging and ischemia-reperfusion injury , 2012, Autophagy.

[21]  Xiao-Ming Yin,et al.  Autophagy is cytoprotective during cisplatin injury of renal proximal tubular cells. , 2008, Kidney international.

[22]  Hideyuki Okano,et al.  Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice , 2006, Nature.

[23]  Robert Clarke,et al.  Guidelines for the use and interpretation of assays for monitoring autophagy , 2012 .

[24]  Govind Bhagat,et al.  Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. , 2003, The Journal of clinical investigation.

[25]  N. Mizushima,et al.  Methods in Mammalian Autophagy Research , 2010, Cell.

[26]  D. Klionsky.  A human autophagy interaction network , 2012, Autophagy.

[27]  A F Slater,et al.  Chloroquine: mechanism of drug action and resistance in Plasmodium falciparum. , 1993, Pharmacology & therapeutics.

[28]  William A Weiss,et al.  Principles and Current Strategies for Targeting Autophagy for Cancer Treatment , 2011, Clinical Cancer Research.

[29]  H. Rakugi,et al.  Cardiovascular , Pulmonary , and Renal Pathology Autophagy Guards Against Cisplatin-Induced Acute Kidney Injury , 2012 .

[30]  G. Deray,et al.  Prevention of cisplatin nephrotoxicity: state of the art and recommendations from the European Society of Clinical Pharmacy Special Interest Group on Cancer Care , 2008, Cancer Chemotherapy and Pharmacology.

[31]  Z. Dong,et al.  Cisplatin nephrotoxicity: mechanisms and renoprotective strategies. , 2008, Kidney international.

[32]  R. Kurzrock,et al.  Autophagy as a target for anticancer therapy , 2011, Nature Reviews Clinical Oncology.

[33]  Arnold J. Levine,et al.  Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[34]  Masaaki Komatsu,et al.  Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice , 2005, The Journal of cell biology.

[35]  Yasushi Matsumura,et al.  The role of autophagy in cardiomyocytes in the basal state and in response to hemodynamic stress , 2007, Nature Medicine.