Tyrosine phosphatase inhibitor-3 sensitizes melanoma and colon cancer to biotherapeutics and chemotherapeutics.
Drug resistance is a major obstacle in cancer treatments and diminishes the clinical efficacy of biological, cytotoxic, or targeted therapeutics. Being an antiapoptotic mediator of chemoresistance in breast and lung cancer cells, MKP1 phosphatase might be targeted for overcoming chemoresistance and improving therapeutic efficacy. In this work, tyrosine phosphatase inhibitor-3 (TPI-3) was identified as a novel small molecule inhibitor of MKP1 and was capable of sensitizing tumors to bio- and chemotherapeutics in mice as a tolerated oral agent. Effective against recombinant MKP1, TPI-3 selectively increased MKP1 phosphosubstrates in Jurkat cells and induced cell death via apoptosis at nanomolar concentrations. TPI-3 also increased MKP1 phosphosubstrates in WM9 human melanoma cells and synergized with biotherapeutic IFN alpha 2b in the growth inhibition of melanoma cells in vitro (combination index, <1). WM9 xenografts unresponsive to individual agents were significantly inhibited (62%, P = 0.001) in mice by a tolerated combination of oral TPI-3 (10 mg/kg, 5 d/wk) and IFN alpha 2b. MKP1 expression was detected in human melanoma cell lines and tissue samples at levels up to six times higher than those in normal or nonmalignant melanocytes. TPI-3 also interacted positively with chemotherapeutics, 5-fluorouracil/leucovorin, against MC-26 colon cancer cells in vitro and in mice. Altogether, our data show the preclinical activities of TPI-3 in overcoming cancer resistance to bio- and chemotherapeutics, implicate MKP1 as a drug-resistant molecule in melanoma, and support the targeting of MKP1 for improving cancer therapeutic efficacy.
Kundu
Suman
S
Department of Cancer Biology, Lerner Research Institute, The Cleveland Clinic, 9500 Euclid Avenue, NB4-67, Cleveland, OH 44195, USA.
Fan
Keke
K
Cao
Mingli
M
Lindner
Daniel J
DJ
Tuthill
Ralph
R
Liu
Lili
L
Gerson
Stanton
S
Borden
Ernest
E
Yi
Taolin
T
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D054638:Dual Specificity Phosphatase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D005472:Fluorouracil / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000494:pharmacology / Q000627:therapeutic use*; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D051379:Mice; D011994:Recombinant Proteins; D013379:Substrate Specificity / Q000187:drug effects; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D013844:Thiazoles; C553668:tyrosine phosphatase inhibitor-3; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1; D005472:Fluorouracil