Antitumor and antimetastatic activities of chloroquine diphosphate in a murine model of breast cancer.
Metastatic breast cancers are hard to treat and almost always fatal. Chloroquine diphosphate, a derivative of quinine, has long been used as a potent and commonly used medicine against different human diseases. We therefore investigated the effects of chloroquine diphosphate on a highly metastatic mouse mammary carcinoma cell line. In vitro treatment of 4T1 mouse breast cancer cells with chloroquine diphosphate resulted in significant inhibition of cellular proliferation and viability, and induction of apoptosis in 4T1 cells in a time- and dose-dependent manner. Further analysis indicated that induction of apoptosis was associated with the loss of mitochondrial membrane potential, release of cytochrome c, and activation of caspase-9 and caspase-3, and cleavage of poly(ADP-ribose) polymerase. The effect of chloroquine diphosphate was then examined using a mice model in which 4T1 cells were implanted subcutaneously. Chloroquine diphosphate (25mg/kg and 50mg/kg, respectively) significantly inhibited the growth of the implanted 4T1 tumor cells and induced apoptosis in the tumor microenvironment. Moreover, the metastasis of tumor cells to the lungs was inhibited significantly and the survival of the mice enhanced. These data suggested that chloroquine diphosphate might have chemotherapeutic efficacy against breast cancer including inhibition of metastasis.
Jiang
Pei-Du
PD
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, No. 1 Keyuan Road 4, Gaopeng Street, High Technological Development Zone, Chengdu, Sichuan 610041, People's Republic of China.
Zhao
Ying-Lan
YL
Deng
Xiao-Qiang
XQ
Mao
Yong-Qiu
YQ
Shi
Wei
W
Tang
Qing-Qing
QQ
Li
Zheng-Guang
ZG
Zheng
Yu-Zhu
YZ
Yang
Sheng-Yong
SY
Wei
Yu-Quan
YQ
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002738:Chloroquine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D045304:Cytochromes c / Q000378:metabolism; D005260:Female; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis / Q000188:drug therapy*; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D000970:Antineoplastic Agents; D011064:Poly Adenosine Diphosphate Ribose; C023676:chloroquine diphosphate; D002738:Chloroquine; D045304:Cytochromes c; D053148:Caspase 3; D053453:Caspase 9