The Antiproliferative and Colony-suppressive Activities of STAT3 Inhibitors in Human Cancer Cells Is Compromised Under Hypoxic Conditions.
Constitutive activation of signal transducer and activator of transcription 3 (STAT3) has been indicated as a novel cancer drug target, since it plays an important role in diverse oncogenic processes including survival, cell proliferation and migration. Emerging STAT3 inhibitors have demonstrated efficacy in cancer cells and animal tumor models. It is well known that most solid tumors are characterized by hypoxia, but it is not clear if hypoxic conditions affect activity of STAT3 inhibitors. To examine this, two STAT3 inhibitors were tested to investigate their inhibitory efficacy in cancer cells grown under hypoxic conditions compared with those without hypoxia. Cell proliferation, colony formation and western blot assays were performed to examine the differences in the cell viability, proliferation and proteins in the STAT3 pathway. Under hypoxic conditions, the half-maximal inhibitory concentration values for both STAT3 inhibitors were increased compared to normoxic conditions in human pancreatic cancer, medulloblastoma and sarcoma cell lines. In addition, the ability of both STAT3 inhibitors to inhibit colony formation in pancreatic cancer, medulloblastoma and sarcoma cell lines was reduced under hypoxic conditions when compared to cells under normoxic conditions. Furthermore, there was an increase in phosphorylated STAT3 levels in cancer cells under hypoxic conditions, suggesting this may be one of the mechanisms of resistance. In summary, the results presented here provide a novel finding of STAT3 inhibitor activity under hypoxic conditions and indicate that under such low oxygen conditions, the anticancer efficacy of STAT3 inhibitors was indeed hampered. These results highlight the need to develop new therapeutic strategies to overcome the resistance of cancer cells to STAT3 inhibitors under hypoxic conditions.
State Key Laboratory of Bioelectronics, Jiangsu Key Laboratory for Biomaterials and Devices, School of Biological Science and Medical Engineering, Southeast University, Nanjing, Jiangsu, P.R. China.|Collaborative Innovation Center of Suzhou Nano-Science and Technology, Suzhou Key Laboratory of Biomaterials and Technologies, Suzhou, Jiangsu, P.R. China.|Department of Biochemistry and Molecular Biology, School of Medicine, University of Maryland, Baltimore, MD, U.S.A.
Jilai
J
Tian
Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, OH, U.S.A.
Hui
H
Xiao
Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, OH, U.S.A.
Ruohan
R
Wu
Department of Hematology & Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China.
Yang
Y
Cao
Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH, U.S.A.
Chenglong
C
Li
Department of Precision Machinery and Precision Instrumentation, University of Science and Technology of China, Hefei, Anhui, P.R. China.|Department of Biomedical Engineering, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, U.S.A.
Ronald
R
Xu
Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, and Departments of Pathology and Biomedical Education & Anatomy, College of Medicine, The Ohio State University, Columbus, OH, U.S.A.
Christopher R
CR
Pierson
Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, OH, U.S.A.|Hematology and Oncology, The Research Institute at Nationwide Children's Hospital, Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, OH, U.S.A.
Jonathan L
JL
Finlay
State Key Laboratory of Bioelectronics, Jiangsu Key Laboratory for Biomaterials and Devices, School of Biological Science and Medical Engineering, Southeast University, Nanjing, Jiangsu, P.R. China.|Collaborative Innovation Center of Suzhou Nano-Science and Technology, Suzhou Key Laboratory of Biomaterials and Technologies, Suzhou, Jiangsu, P.R. China.
Fang
F
Yang
State Key Laboratory of Bioelectronics, Jiangsu Key Laboratory for Biomaterials and Devices, School of Biological Science and Medical Engineering, Southeast University, Nanjing, Jiangsu, P.R. China.|Collaborative Innovation Center of Suzhou Nano-Science and Technology, Suzhou Key Laboratory of Biomaterials and Technologies, Suzhou, Jiangsu, P.R. China.
Ning
N
Gu
Department of Biochemistry and Molecular Biology, School of Medicine, University of Maryland, Baltimore, MD, U.S.A. JLin@som.umaryland.edu.
Jiayuh
J
Lin
D000631:Aminopyridines / Q000494:pharmacology*; D000880:Anthraquinones / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D048708:Cell Growth Processes / Q000187:drug effects; D015687:Cell Hypoxia / Q000502:physiology*; D045744:Cell Line, Tumor; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000187:drug effects; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors*; D013449:Sulfonamides / Q000494:pharmacology*
C582914:5,8-dioxo-6-(pyridin-3-ylamino)-5,8-dihydronaphthalene-1-sulfonamide; D000631:Aminopyridines; D000880:Anthraquinones; D000970:Antineoplastic Agents; C549232:LLL12 compound; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D013449:Sulfonamides
STAT3; STAT3 inhibitor; drug resistance; hypoxia