The four-herb Chinese medicine PHY906 reduces chemotherapy-induced gastrointestinal toxicity.
PHY906, a four-herb Chinese medicine formula first described 1800 years ago, decreases gastrointestinal toxicity induced by the chemotherapeutic drug CPT-11 (irinotecan), as shown in a phase I/II clinical study. Similarly, in a murine colon 38 allograft model, PHY906 increased the antitumor activity of CPT-11 while decreasing animal weight loss caused by CPT-11. Here, we have further examined the effect of PHY906 on the intestinal toxicity caused by CPT-11 in mice. PHY906 did not protect against the initial DNA damage and apoptosis triggered by CPT-11 in the intestine, but by 4 days after CPT-11 treatment, PHY906 had restored the intestinal epithelium by promoting the regeneration of intestinal progenitor or stem cells and several Wnt signaling components. PHY906 also potentiated Wnt3a activity in human embryonic kidney-293 cells. Furthermore, PHY906 exhibited anti-inflammatory effects in mice by decreasing the infiltration of neutrophils or macrophages, tumor necrosis factor-alpha expression in the intestine, and proinflammatory cytokine concentrations in plasma. Chemical constituents of PHY906 potently inhibited nuclear factor kappaB, cyclooxygenase-2, and inducible nitric oxide synthase. Our results show that the herbal medicine PHY906 can counteract the toxicity of CPT-11 via several mechanisms that act simultaneously.
Lam
Wing
W
Yale University School of Medicine, New Haven, CT 06520, USA.
Bussom
Scott
S
Guan
Fulan
F
Jiang
Zaoli
Z
Zhang
Wei
W
Gullen
Elizabeth A
EA
Liu
Shwu-Huey
SH
Cheng
Yung-Chi
YC
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000378:metabolism; D001973:Bromodeoxyuridine / Q000378:metabolism; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000633:toxicity; D049109:Cell Proliferation / Q000187:drug effects; D004249:DNA Damage; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D041981:Gastrointestinal Tract / Q000187:drug effects* / Q000473:pathology* / Q000503:physiopathology; D005966:Glucuronidase / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000473:pathology; D000077146:Irinotecan; D008516:Medicine, Chinese Traditional; D051379:Mice; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D020127:Recovery of Function / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism; D014184:Transplantation, Homologous; D015431:Weight Loss / Q000187:drug effects; D051153:Wnt Proteins / Q000378:metabolism; D060508:Wnt3 Protein; D060509:Wnt3A Protein; D051176:beta Catenin / Q000378:metabolism
D000972:Antineoplastic Agents, Phytogenic; D014408:Biomarkers, Tumor; D004365:Drugs, Chinese Herbal; C476037:PHY 906; D018809:Proliferating Cell Nuclear Antigen; C555510:WNT3A protein, human; D051153:Wnt Proteins; D060508:Wnt3 Protein; D060509:Wnt3A Protein; C555511:Wnt3a protein, mouse; D051176:beta Catenin; D000077146:Irinotecan; D005966:Glucuronidase; D001973:Bromodeoxyuridine; D002166:Camptothecin