title: Nexrutine(R) inhibits tumorigenesis in mouse skin and induces apoptotic cell death in human squamous carcinoma A431 and human melanoma A375 cells.
abstract: Nexrutine(®) (NX), a herbal extract from Phellodendron amurense, has been shown to possess antitumor, antimicrobial, anti-inflammatory and other biological activities. In the present investigation, we explored the mechanism of chemopreventive/chemotherapeutic efficacy of NX against skin cancer. Single application of NX (1.0mg/mouse) prior to 12-O-tetradecanoylphorbol 13-acetate (TPA) application significantly inhibited TPA-induced skin edema, hyperplasia, thymidine incorporation and ornithine decarboxylase (ODC) activity; expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS); phosphorylation of extracellular signal-regulated kinases (ERK) 1/2, p38 and c-jun N-terminal kinase (JNK) mitogen-activated protein kinases (MAPKs); and activation of I kappa B kinase (IKK), IκBα and nuclear factor-kappa B (NF-κB) in mouse skin. In a two-stage mouse skin tumorigenesis model, it was found that twice-weekly treatment of NX prior to TPA application in 7,12-dimethylbenz[α]anthracene (DMBA)-initiated animals showed reduced tumor incidence, lower tumor body burden and significant delay in latency period compared with DMBA-initiated and TPA-promoted animals. Furthermore, the therapeutic efficacy of NX was assessed against human squamous carcinoma (A431) and human melanoma (A375) cells. A431 and A375 cells treated with NX (2.5-10.0 μg/ml, 48h) showed a decrease in viability and enhanced cell cycle arrest at the G(0)/G(1) phase and apoptosis; however, NX had minimal cytotoxic effect on HaCaT cells and primary murine keratinocytes, suggesting its high therapeutic index. In addition, NX treatment also modulates the levels of Bax and Bcl-2 proteins along with cytochrome c release, cleavage and enhanced expression of poly (adenosine diphosphate-ribose) polymerase as well as catalytic activities of caspases 3 and 9 in both A431 and A375 cells. Based on our in vivo and in vitro studies, NX could be useful in the management (chemoprevention as well as chemotherapy) of skin cancer.
authors: CSIR-Indian Institute of Toxicology Research, Lucknow, India.
authors: Rahul
authors: R
authors: Kumar
authors: Mukul
authors: M
authors: Das
authors: Kausar M
authors: KM
authors: Ansari
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D017209:Apoptosis; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000517:prevention & control*; D045744:Cell Line, Tumor; D006801:Humans; D008545:Melanoma / Q000188:drug therapy / Q000517:prevention & control*; D051379:Mice; D010936:Plant Extracts / Q000494:pharmacology*; D012878:Skin Neoplasms / Q000139:chemically induced / Q000188:drug therapy / Q000517:prevention & control*; D013755:Tetradecanoylphorbol Acetate
chemical_list: D000893:Anti-Inflammatory Agents; D016588:Anticarcinogenic Agents; C512605:Nexrutine; D010936:Plant Extracts; D013755:Tetradecanoylphorbol Acetate