cyclin-d1 and Neurofibromatosis-1

Neurofibromatosis type 1 (NF1) patients are prone to the development of malignant tumors, the most common being Malignant Peripheral Nerve Sheath Tumor (MPNST). NF1-MPNST patients have an overall poor survival due to systemic metastasis. Currently, the management of MPNSTs includes surgery and radiation; however, conventional chemotherapy is not very effective, underscoring the need for effective biologically-targeted therapies. Recently, the NF1 gene product, neurofibromin, was shown to negatively regulate the phosphoinositide-3-kinase (PI3K)/Protein Kinase-B (Akt)/mammalian Target Of Rapamycin (mTOR) pathway, with loss of neurofibromin expression in established human MPNST cell lines associated with high levels of mTOR activity. We developed and characterized a human NF1-MPNST explant grown subcutaneously in NOD-SCID mice, to evaluate the effect of the mTOR inhibitor rapamycin. We demonstrate that rapamycin significantly inhibited human NF1-MPNST mTOR pathway activation and explant growth in vivo at doses as low as 1.0 mg/kg/day, without systemic toxicities. While rapamycin was effective at reducing NF1-MPNST proliferation and angiogenesis, with decreased CyclinD1 and VEGF respectively, there was no increase in tumor apoptosis. Rapamycin effectively decreased activation of S6 downstream of mTOR, but there was accompanied increased Akt activation. This study demonstrates the therapeutic potential and limitations of rapamycin in NF1-associated, and likely sporadic, MPNSTs.

Topics: Animals; Antibiotics, Antineoplastic; Apoptosis; Blotting, Western; Cyclin D1; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Humans; Immunohistochemistry; Male; Mice; Mice, Inbred NOD; Mice, SCID; Neurofibromatosis 1; Peripheral Nervous System Neoplasms; Protein Kinases; Proto-Oncogene Proteins c-akt; Ribosomal Protein S6 Kinases; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Tumor Burden; Vascular Endothelial Growth Factor A; Xenograft Model Antitumor Assays; Young Adult

There is increasing evidence that more than 70% of cancers including pancreatic, breast and prostate cancers as well as neurofibromatosis (NF) are highly addicted to abnormal activation of the Ser/Thr kinase PAK1 for their growth. So far FK228 is the most potent among the HDAC (histone deacetylase) inhibitors that block the activation of both PAK1 and another kinase AKT, downstream of PI-3 kinase. However, FK228 is still in clinical trials (phase 2) for a variety of cancers (but not for NF as yet), and not available for most cancer/NF patients. Thus, we have been exploring an alternative which is already in the market, and therefore immediately useful for the treatment of those desperate cancer/NF patients. Here we provide the first evidence that extracts of Chinese/ Japanese peppercorns (Zanthoxyli Fructus) from the plant Zanthoxylum piperitum called "Hua Jiao"/"Sansho", block selectively the key kinase PAK1, leading to the downregulation of cyclin D1. Unlike FK228, these extracts do not inhibit AKT activation at the concentrations that block either cancer growth or PAK1 activation. The Chinese pepper extract selectively inhibits the growth of NF1-deficient malignant peripheral nerve sheath tumor (MPNST) cells, without affecting the growth of normal fibroblasts, and suppresses the growth of NF1-deficient human breast cancer (MDA-MB-231) xenograft in mice. Our data suggest that these peppercorn extracts would be potentially useful for the treatment of PAK1-dependent NF such as MPNST, in addition to a variety of PAK1-dependent cancers including breast cancers.

Topics: Animals; Antimitotic Agents; Cell Line, Tumor; Cell Proliferation; Cyclin D1; Down-Regulation; Enzyme Inhibitors; Female; Humans; Mice; Mice, Inbred BALB C; Neoplasm Transplantation; Nerve Sheath Neoplasms; Neurofibromatosis 1; Neurofibromin 1; p21-Activated Kinases; Phytotherapy; Plant Extracts; Protein Serine-Threonine Kinases; Signal Transduction; Transplantation, Heterologous; Zanthoxylum

Plexiform neurofibroma (PNF) has a low potential to undergo malignant transformation. Identification of markers associated with tumor progression is important since it may serve as prognostic indicators or adjuncts to standard pathological examination. In the present study, the authors immunostained 20 neurofibromatosis type I-associated PNFs with cyclinD1, p27kip-1, and bcl-2. Six of the cases had progressed into malignant peripheral nerve sheath tumor (MPNST), and the transitional area of each sample was also stained separately in order to identify protein(s) associated with tumor progression. Cyclin D1 was found to be significantly increased in the transitional zone, compared to the ordinary PNF (p = 0.007). The protein is, thus, likely to play a role in the malignant transformation. There was no significant difference in the expression of p27kip-1 and bcl-2 during the malignant progression of PNF.

Topics: Adolescent; Adult; Biomarkers, Tumor; Cell Transformation, Neoplastic; Child; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p27; Disease Progression; Female; Humans; Immunohistochemistry; Intracellular Signaling Peptides and Proteins; Male; Middle Aged; Neurofibroma, Plexiform; Neurofibromatosis 1; Proto-Oncogene Proteins c-bcl-2