title: Cucurbitacin D induces cell cycle arrest and apoptosis by inhibiting STAT3 and NF-κB signaling in doxorubicin-resistant human breast carcinoma (MCF7/ADR) cells.
abstract: Breast cancer is the most common cancer for women and is a major cause of mortality in women. Doxorubicin is a generally used chemotherapy drug for breast cancer. However, multidrug resistance of breast cancer interferes with the chemotherapy. We examined whether cucurbitacin D affects doxorubicin resistance of MCF7/ADR breast cancer cells. Cell viability was measured by MTT assay. Levels of p-STAT3, p-NF-κB, IκB, and caspases were measured by Western blot analysis. Nuclear staining of Stat3 and NF-κB was measured by immunocytochemistry. STAT3 and NF-κB transcriptional activity was detected by STAT3 and NF-κB luciferase reporter gene assays. Analysis of cell cycle arrest was performed by flow cytometry. Induction of apoptosis by cucurbitacin D was measured by Annexin V-FITC/propidium iodide assay. More than 90% of MCF7/ADR cells lived upon treatment with doxorubicin for 24 h. However, upon treatment with cucurbitacin D, cell death was more than 60%. Co-administration of cucurbitacin D and doxorubicin induced apoptosis, and G2/M cell cycle arrest, and inhibited upregulated Stat3 by doxorubicin on MCF7/ADR cells. Additionally, cucurbitacin D led to an increase in the IκBα level in the cytosol and a decrease in the p-NF-κB level in the nucleus. Finally, cucurbitacin D inhibited translocation of Stat3 and NF-κB and decreased transcriptional activity in the nucleus. Cucurbitacin D decreases cell proliferation and induces apoptosis by inhibiting Stat3 and NF-κB signaling in doxorubicin-resistant breast cancer cells. Cucurbitacin D could be used as a useful compound to treat adriamycin-resistant patients.
authors.affiliation: Laboratory of Clinical Biology and Pharmacogenomics, Department of Preventive Medicine, College of Oriental Medicine, Kyung Hee University, Seoul, 130-701, Republic of Korea.
authors.forename: Jin Mo
authors.initials: JM
authors.lastname: Ku
authors.affiliation: Laboratory of Clinical Biology and Pharmacogenomics, Department of Preventive Medicine, College of Oriental Medicine, Kyung Hee University, Seoul, 130-701, Republic of Korea.
authors.forename: Soon Re
authors.initials: SR
authors.lastname: Kim
authors.affiliation: Laboratory of Clinical Biology and Pharmacogenomics, Department of Preventive Medicine, College of Oriental Medicine, Kyung Hee University, Seoul, 130-701, Republic of Korea.
authors.forename: Se Hyang
authors.initials: SH
authors.lastname: Hong
authors.affiliation: Laboratory of Clinical Biology and Pharmacogenomics, Department of Preventive Medicine, College of Oriental Medicine, Kyung Hee University, Seoul, 130-701, Republic of Korea.
authors.forename: Han-Seok
authors.initials: HS
authors.lastname: Choi
authors.affiliation: Laboratory of Clinical Biology and Pharmacogenomics, Department of Preventive Medicine, College of Oriental Medicine, Kyung Hee University, Seoul, 130-701, Republic of Korea.
authors.forename: Hye Sook
authors.initials: HS
authors.lastname: Seo
authors.affiliation: Laboratory of Clinical Biology and Pharmacogenomics, Department of Preventive Medicine, College of Oriental Medicine, Kyung Hee University, Seoul, 130-701, Republic of Korea.
authors.forename: Yong Cheol
authors.initials: YC
authors.lastname: Shin
authors.affiliation: Laboratory of Clinical Biology and Pharmacogenomics, Department of Preventive Medicine, College of Oriental Medicine, Kyung Hee University, Seoul, 130-701, Republic of Korea. epiko@khu.ac.kr.
authors.forename: Seong-Gyu
authors.initials: SG
authors.lastname: Ko
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D061986:MCF-7 Cells; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014315:Triterpenes / Q000494:pharmacology*
chemical_list: D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D014315:Triterpenes; D000072000:NF-KappaB Inhibitor alpha; C038105:cucurbitacin D; D004317:Doxorubicin; D020169:Caspases
keywords: Breast cancer; Cucurbitacin D; Doxorubicin; MCF7 cell; MCF7/ADR cell; Multidrug resistance