Journal Article

Nexrutine<sup>®</sup> inhibits tumorigenesis in mouse skin and induces apoptotic cell death in human squamous carcinoma A431 and human melanoma A375 cells

Rahul Kumar, Mukul Das and Kausar M. Ansari

in Carcinogenesis

Volume 33, issue 10, pages 1909-1918
Published in print October 2012 | ISSN: 0143-3334
Published online July 2012 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgs219
Nexrutine® inhibits tumorigenesis in mouse skin and induces apoptotic cell death in human squamous carcinoma A431 and human melanoma A375 cells

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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 G0/G1 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.

Journal Article.  6827 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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