Paris saponin VII inhibits growth of colorectal cancer cells through Ras signaling pathway.
Dysregulation of the Ras signaling pathway plays a key role in the progression of colorectal cancer. When bound to GTP, Ras is activated and stimulates several downstream effectors' pathways, including the Raf/MEK/ERK kinase cascade, the PI3-kinase/AKT/mTor pathway, and the Ral GTPase pathway. Saponins extracted from Liliaceae family herbs have strong antitumor activities with low toxicity. In this study, Paris saponin VII (PSVII), isolated from Trillium tschonoskii Maxim., was evaluated on human colorectal cancer cells (HT-29 and SW-620), a mouse model of colitis associated colorectal cancer (CACC) and a murine model of xenograft tumor. It was found that PSVII inhibited colorectal cancer cell growth in a concentration-dependent manner. The IC50 values of PSVII for growth inhibition of HT-29 and SW-620 cells were 1.02 ± 0.05 μM and 4.90 ± 0.23 μM. It could induce cell apoptosis, together with cell cycle arrest in G1 phase, and trigger apoptosis in a caspase-3-dependent manner. PSVII-induced growth inhibitory effect was associated with disturbance of MAPK pathway by down-regulating MEK1/2, ERK1/2 phosphorylation, and suppression of AKT pathway by reducing AKT and GSK-3β phosphorylation. In the CACC mouse model, PSVII protected mice from intestinal toxicities and carcinogenesis induced by 1,2-dimethylhydrazine (DMH) and dextran sodium sulfate (DSS). In the model of xenograft tumor, PSVII remarkably decreased the xenograft tumor size and triggered the apoptosis of tumor cells. Both in vitro and in vivo study showed that PSVII inhibited Ras activity. Taken together, PSVII might be a potential therapeutic reagent for colorectal cancer through targeting Ras signaling pathway.
No. 422 Hospital of PLA, Zhanjiang 524005, Guangdong, PR China; Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, Collaborative Innovation Center for Chinese Medicine in Qinba Mountains, Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi'an 710032, Shaanxi, PR China.
Yuhua
Y
Li
Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, Collaborative Innovation Center for Chinese Medicine in Qinba Mountains, Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi'an 710032, Shaanxi, PR China.
Yang
Y
Sun
Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, Collaborative Innovation Center for Chinese Medicine in Qinba Mountains, Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi'an 710032, Shaanxi, PR China.
Lei
L
Fan
Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, Collaborative Innovation Center for Chinese Medicine in Qinba Mountains, Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi'an 710032, Shaanxi, PR China.
Feng
F
Zhang
Department of Pharmacy, No. 309 Hospital of PLA, Beijing 100000, PR China.
Jin
J
Meng
Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, Collaborative Innovation Center for Chinese Medicine in Qinba Mountains, Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi'an 710032, Shaanxi, PR China.
Jin
J
Han
Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, VA 23507, USA.
Xin
X
Guo
Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, Collaborative Innovation Center for Chinese Medicine in Qinba Mountains, Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi'an 710032, Shaanxi, PR China.
Dian
D
Zhang
Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, Collaborative Innovation Center for Chinese Medicine in Qinba Mountains, Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi'an 710032, Shaanxi, PR China.
Rong
R
Zhang
Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, Collaborative Innovation Center for Chinese Medicine in Qinba Mountains, Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi'an 710032, Shaanxi, PR China. Electronic address: 1547223183@qq.com.
Zhenggang
Z
Yue
Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, Collaborative Innovation Center for Chinese Medicine in Qinba Mountains, Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi'an 710032, Shaanxi, PR China. Electronic address: qbmei53@hotmail.com.
Qibing
Q
Mei
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D011905:Genes, ras / Q000187:drug effects / Q000502:physiology*; D006131:Growth Inhibitors / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use*; D019073:HT29 Cells; D006801:Humans; D051379:Mice; D008813:Mice, Inbred ICR; D008819:Mice, Nude; D010936:Plant Extracts / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use; D012503:Saponins / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D031446:Trillium; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D000972:Antineoplastic Agents, Phytogenic; D006131:Growth Inhibitors; D010936:Plant Extracts; D012503:Saponins
Apoptosis; Colorectal cancer (CRC); Paris saponin VII (PSVII); Ras