title: MAPK signaling mediates sinomenine hydrochloride-induced human breast cancer cell death via both reactive oxygen species-dependent and -independent pathways: an in vitro and in vivo study.
abstract: Sinomenine, the main alkaloid extracted from the medicinal plant Sinomenium acutum, is known for its anti-inflammatory effects. Recent studies have suggested its anti-cancer effect in synovial sarcoma, lung cancer and hepatic cancer. However, the underlying molecular mechanism for its anti-cancer effect still remains unclear. This study investigated the anti-tumor activity of sinomenine hydrochloride (SH), a hydrochloride form of sinomenine, in human breast cancer cells in vitro and in vivo. We found that SH potently inhibited cell viability of a broad panel of breast cancer cell lines. Two representative breast cancer cell lines, namely ER(-)/PR(-) MDA-MB-231 and ER(+)/PR(+) MCF-7, were used for further investigation. The results showed that SH induced G1/S cell cycle arrest, caused apoptosis and induced ATM/Chk2- and ATR/Chk1-mediated DNA-damage response in MDA-MB-231 and MCF-7. The anti-cancer effect of SH was regulated by increased expression levels of p-ERK, p-JNK and p-38 MAPK. Further studies showed that SH resulted in an increase in reactive oxygen species (ROS) and inhibition of ROS by N-acetyl-L-cysteine (NAC) almost blocked SH-induced DNA damage but only mitigated SH-induced MAPK expression changes, suggesting that both ROS-dependent and -independent pathways were involved in MAPK-mediated SH-induced breast cancer cell death. The in vivo study demonstrated that SH effectively inhibited tumor growth without showing significant toxicity. In conclusion, SH induced breast cancer cell death through ROS-dependent and -independent pathways with an upregulation of MAPKs, indicating that SH may be a potential anti-tumor drug for breast cancer treatment.
authors: Department of Surgical Oncology, First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, P.R. China.
authors: X
authors: X
authors: Li
authors: Department of Surgical Oncology, First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, P.R. China.
authors: K
authors: K
authors: Wang
authors: Department of Surgical Oncology, First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, P.R. China.
authors: Y
authors: Y
authors: Ren
authors: Department of Surgical Oncology, First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, P.R. China.
authors: L
authors: L
authors: Zhang
authors: Department of Surgical Oncology, First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, P.R. China.
authors: X-J
authors: XJ
authors: Tang
authors: Department of Surgical Oncology, First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, P.R. China.
authors: H-M
authors: HM
authors: Zhang
authors: Key Laboratory of Cell Proliferation and Regulation Biology, College of Life Science, Beijing Normal University, Beijing, P.R. China.
authors: C-Q
authors: CQ
authors: Zhao
authors: Translational Medical center, First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, P.R. China.
authors: P-J
authors: PJ
authors: Liu
authors: 1] Translational Medical center, First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, P.R. China [2] Department of Cancer Genetics, Roswell Park Cancer Institute, Elm and Calton Streets, Buffalo, NY, USA.
authors: J-M
authors: JM
authors: Zhang
authors: Department of Surgical Oncology, First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, P.R. China.
authors: J-J
authors: JJ
authors: He
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008807:Mice, Inbred BALB C; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D009019:Morphinans / Q000008:administration & dosage*; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D009019:Morphinans; D017382:Reactive Oxygen Species; C009271:sinomenine; D020929:Mitogen-Activated Protein Kinase Kinases