Inhibition of the JAK-STAT3 pathway by andrographolide enhances chemosensitivity of cancer cells to doxorubicin.
Andrographolide (Andro), a diterpenoid lactone isolated from a traditional herbal medicine Andrographis paniculata, is known to possess potent anti-inflammatory and anticancer properties. In this study, we sought to examine the effect of Andro on signal transducer and activator of transcription 3 (STAT3) pathway and evaluate whether suppression of STAT3 activity by Andro could sensitize cancer cells to a chemotherapeutic drug doxorubicin. First, we demonstrated that Andro is able to significantly suppress both constitutively activated and IL-6-induced STAT3 phosphorylation and subsequent nuclear translocation in cancer cells. Such inhibition is found to be achieved through suppression of Janus-activated kinase (JAK)1/2 and interaction between STAT3 and gp130. For understanding the biological significance of the inhibitory effect of Andro on STAT3, we next investigated the effect of Andro on doxorubicin-induced apoptosis in human cancer cells. In our study the constitutive activation level of STAT3 was found to be correlated to the resistance of cancer cells to doxorubicin-induced apoptosis. Both the short-term MTT assay and the long-term colony formation assay showed that Andro dramatically promoted doxorubicin-induced cell death in cancer cells, indicating that Andro enhances the sensitivity of cancer cells to doxorubicin mainly via STAT3 suppression. These observations thus reveal a novel anticancer function of Andro and suggest a potential therapeutic strategy of using Andro in combination with chemotherapeutic agents for treatment of cancer.
Zhou
Jing
J
Department of Epidemiology and Public Health, Yong Loo Lin School of Medicine, National University of Singapore, 16 Medical Drive, Singapore 117597, Republic of Singapore.
Ong
Choon-Nam
CN
Hur
Gang-Min
GM
Shen
Han-Ming
HM
D045744:Cell Line, Tumor; D004224:Diterpenes / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D006801:Humans; D053612:Janus Kinases / Q000378:metabolism*; D010766:Phosphorylation; D050796:STAT3 Transcription Factor / Q000378:metabolism*
D004224:Diterpenes; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C030419:andrographolide; D004317:Doxorubicin; D053612:Janus Kinases