Enhancing tumor-specific uptake of the anticancer drug cisplatin with a copper chelator.
Uptake of the anticancer drug cisplatin is mediated by the copper transporter CTR1 in cultured cells. Here we show in human ovarian tumors that low levels of Ctr1 mRNA are associated with poor clinical response to platinum-based therapy. Using a mouse model of human cervical cancer, we demonstrate that combined treatment with a copper chelator and cisplatin increases cisplatin-DNA adduct levels in cancerous but not in normal tissues, impairs angiogenesis, and improves therapeutic efficacy. The copper chelator also enhances the killing of cultured human cervical and ovarian cancer cells with cisplatin. Our results identify the copper transporter as a therapeutic target, which can be manipulated with copper chelating drugs to selectively enhance the benefits of platinum-containing chemotherapeutic agents.
Ishida
Seiko
S
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA.
McCormick
Frank
F
Smith-McCune
Karen
K
Hanahan
Douglas
D
D000251:Adenosine Triphosphatases / Q000235:genetics; D000277:Adjuvants, Pharmaceutic / Q000494:pharmacology*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000825:Animal Structures / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D016190:Carboplatin / Q000627:therapeutic use; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002614:Chelating Agents / Q000378:metabolism / Q000494:pharmacology*; D002945:Cisplatin / Q000378:metabolism* / Q000627:therapeutic use*; D003300:Copper / Q000097:blood / Q000378:metabolism*; D000079923:Copper Transporter 1; D000073840:Copper-Transporting ATPases; D018736:DNA Adducts / Q000378:metabolism; D004195:Disease Models, Animal; D018572:Disease-Free Survival; D005260:Female; D015870:Gene Expression / Q000235:genetics; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D008875:Middle Aged; D008982:Molybdenum / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism; D016896:Treatment Outcome; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology
D000277:Adjuvants, Pharmaceutic; C486201:Atp7a protein, mouse; D027682:Cation Transport Proteins; D002614:Chelating Agents; D000079923:Copper Transporter 1; D018736:DNA Adducts; C490079:SLC31A1 protein, human; D003300:Copper; D008982:Molybdenum; C020809:tetrathiomolybdate; D016190:Carboplatin; D000251:Adenosine Triphosphatases; D000073840:Copper-Transporting ATPases; D002945:Cisplatin