title: Ginsenoside 20(S)-Rh2 exerts anti-cancer activity through targeting IL-6-induced JAK2/STAT3 pathway in human colorectal cancer cells.
abstract: BACKGROUND
  Panax ginseng is one of the most well-known medicinal herbs in Korea and China, which has been used for treatment and prevention of cancer, obesity, diabetes, and cardiovascular diseases. Ginsenosides are the major components of P. ginseng, having a wide range of pharmacological activities. Among the ginsenosides, protopanaxadiol (PPD)-types reportedly have potent anti-cancer effects. Rh2 is PPD-type ginsenoside, and two stereoisomeric forms of Rh2 as 20(S)- and 20(R)-Rh2 were selectively isolated recently.
  
  
  OBJECTIVE
  The biological activities of Rh2 ginsenosides are known to depend on their differences in stereochemistry. Colorectal cancer (CRC) is one of the most lethal neoplasm, and cancer-related death is usually associated with metastasis to other organs. We aimed this study to investigate whether 20(S)- and 20(R)-Rh2 can suppress tumor invasion in human CRC cells.
  
  
  METHODS
  20(S)- and 20(R)-Rh2 were isolated from the roots of ginseng. Human CRC cells were incubated with 20(S)- or 20(R)-Rh2 in the presence or absence of interleukin-6. An MTT assay was used to measure cell viability. Western blot and quantitative real-time PCR analyses were performed to determine levels of expression and phosphorylation. An invasion assay was performed using a Boyden chamber system with the Matrigel-coated membrane to measure cancer cell invasion.
  
  
  RESULTS
  20(S)- and 20(R)-Rh2 showed differential cytotoxic activity. Only 20(S)-Rh2 decreased cancer cell viability. Additionally, 20(S)-Rh2 effectively inhibited IL-6-induced signal transducer and activator of transcription 3 (STAT3) phosphorylation and the expression of matrix metalloproteinases (MMPs), including MMP-1, -2, and -9, resulting in inhibition of cancer cell invasion. Interestingly, these pharmacological activities of 20(S)-Rh2 were more potent than those of 20(R)-Rh2. Furthermore, combination treatment showed that 20(S)-Rh2 enhanced the sensitization of doxorubicin-treated anti-cancer activities in CRC cells.
  
  
  CONCLUSIONS
  Our results demonstrated that ginsenoside 20(S)-Rh2 has therapeutic potential for the treatment with CRC and may be valuable as a combination partner with more classic chemotherapeutic agents, such as doxorubicin, to treat CRC.
authors: Department of Pharmacology and Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Republic of Korea. Electronic address: skysmilez@naver.com.
authors: Songhee
authors: S
authors: Han
authors: Department of Pharmacology and Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Republic of Korea; Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea. Electronic address: lovej89@hotmail.co.kr.
authors: Ae Jin
authors: AJ
authors: Jeong
authors: College of Pharmacy, Kangwon National University, Chuncheon 24341, Republic of Korea. Electronic address: heejyang@kangwon.ac.kr.
authors: Heejung
authors: H
authors: Yang
authors: College of Pharmacy and Research Institute of Pharmaceutical Science, Seoul National University, Seoul 08826, Republic of Korea. Electronic address: mumyung2@snu.ac.kr.
authors: Kyo
authors: K
authors: Bin Kang
authors: Department of Pharmacology and Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Republic of Korea; Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea. Electronic address: hrlee519@gmail.com.
authors: Haeri
authors: H
authors: Lee
authors: Department of Pharmacology and Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Republic of Korea; Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul 03080, Republic of Korea. Electronic address: startwo1204@snu.ac.kr.
authors: Eun Hee
authors: EH
authors: Yi
authors: Department of Pharmacology and Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Republic of Korea; Biomedical Science Project (BK21PLUS), Seoul National University College of Medicine, Seoul 03080, Republic of Korea. Electronic address: protein0826@snu.ac.kr.
authors: Byung-Hak
authors: BH
authors: Kim
authors: Department of Pharmacology and Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Republic of Korea; Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul 03080, Republic of Korea; Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea. Electronic address: iamhyun@snu.ac.kr.
authors: Chung-Hyun
authors: CH
authors: Cho
authors: Department of Biological Science, Dong-A University, Busan 47315, Republic of Korea. Electronic address: jwchung@dau.ac.kr.
authors: Jin Woong
authors: JW
authors: Chung
authors: College of Pharmacy and Research Institute of Pharmaceutical Science, Seoul National University, Seoul 08826, Republic of Korea. Electronic address: shsung@snu.ac.kr.
authors: Sang Hyun
authors: SH
authors: Sung
authors: Department of Pharmacology and Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Republic of Korea; Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul 03080, Republic of Korea; Biomedical Science Project (BK21PLUS), Seoul National University College of Medicine, Seoul 03080, Republic of Korea; Neuro-Immune Information Storage Network Research Center, Seoul National University College of Medicine, Seoul 03080, Republic of Korea. Electronic address: sangkyu@snu.ac.kr.
authors: Sang-Kyu
authors: SK
authors: Ye
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D004357:Drug Synergism; D036145:Ginsenosides / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D015850:Interleukin-6 / Q000502:physiology; D053614:Janus Kinase 2 / Q000378:metabolism*; D020782:Matrix Metalloproteinases / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000093242:Interleukin-6 Inhibitors
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004317:Doxorubicin; D036145:Ginsenosides; D015850:Interleukin-6; D053614:Janus Kinase 2; D020782:Matrix Metalloproteinases; D050796:STAT3 Transcription Factor; D000093242:Interleukin-6 Inhibitors; C494086:STAT3 protein, human; C055305:ginsenoside Rh2; C507924:JAK2 protein, human
keywords: Colorectal cancer (CRC); Ginsenoside 20(S)-Rh2; Interleukin-6 (IL-6); Matrix metalloproteinase (MMP); Signal transducer and activator of transcription 3 (STAT3)