The incidence of melanoma continues to dramatically rise and existing chemotherapeutic strategies have shown little effect against metastatic melanoma. Malignant melanoma is considered a chemotherapy refractory tumor. Currently dacarbazine is the single most active agent against melanoma but has a low response rate of approximately 20%. Even combination therapy such as the Dartmouth regimen, which combines dacarbazine with carmustine, cisplatin, and tamoxifen, achieves a response rate of only 40% (Nathan et al., 2000). Taxol(R) alone has shown a 16% response rate but has considerable toxicity including dose limiting neutropenia as well as peripheral neuropathy (Nathan et al., 2000). For these reasons, more effective and well-tolerated chemotherapeutic agents are needed. Based upon structural similarities to microtubule poisons (colchicine, podophylotoxin, MTC), we identified a tubulin binding natural compound, noscapine (Ye et al., 1998). Our preliminary studies show that noscapine is selectively effective for the treatment of melanoma, prostate, and colon cancer cells in vitro. We propose the following three aims.
Aim 1 proposes studies to understand the binding mechanisms of noscapine with tubulin using high resolution NMR and automated docking algorithms.
Aim 2 will determine the bio-distribution, optimal therapeutic dose, and possible toxicity.
Aim 3 will compare the relative efficacy and toxicity of the noscapine analogs with those of other currently used microtubule agents, Taxol(R), vinblastine, and vinorelbine in prostate and colon cancers. These preclinical studies will be crucial for the future clinical development of this class of promising therapeutic compounds.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA095317-04
Application #
7431746
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Fu, Yali
Project Start
2005-07-01
Project End
2010-05-31
Budget Start
2008-06-01
Budget End
2009-05-31
Support Year
4
Fiscal Year
2008
Total Cost
$257,865
Indirect Cost
Name
Emory University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Suri, Charu; Hendrickson, Triscia W; Joshi, Harish C et al. (2014) Molecular insight into ?-? tubulin lateral interactions within the ?-tubulin ring complex (?-TuRC). J Comput Aided Mol Des 28:961-72
Ajeawung, Norbert F; Mononen, Lotta; Thorn, Andrea et al. (2013) In-Vitro and Ex-Vivo Investigations of the Microtubule Binding Drug Targetin on Angiogenesis. J Pediatr Oncol 1:41-47
Ajeawung, Norbert F; Joshi, Harish C; Kamnasaran, Deepak (2013) Investigation of Targetin, a Microtubule Binding Agent which Regresses the Growth of Pediatric High and Low Grade Gliomas. J Pediatr Oncol 1:32-40
Naik, Pradeep K; Lopus, Manu; Aneja, Ritu et al. (2012) In silico inspired design and synthesis of a novel tubulin-binding anti-cancer drug: folate conjugated noscapine (Targetin). J Comput Aided Mol Des 26:233-47
Naik, Pradeep K; Santoshi, Seneha; Joshi, Harish C (2012) Noscapinoids with anti-cancer activity against human acute lymphoblastic leukemia cells (CEM): a three dimensional chemical space pharmacophore modeling and electronic feature analysis. J Mol Model 18:307-18
Li, Shiwang; Ghaleb, Amr M; He, Jing et al. (2012) Chemoprevention of familial adenomatous polyposis by bromo-noscapine (EM011) in the Apc(Min/+) mouse model. Int J Cancer 131:1435-44
Naik, Pradeep K; Santoshi, Seneha; Rai, Ankit et al. (2011) Molecular modelling and competition binding study of Br-noscapine and colchicine provide insight into noscapinoid-tubulin binding site. J Mol Graph Model 29:947-55
Naik, Pradeep K; Chatterji, Biswa Prasun; Vangapandu, Surya N et al. (2011) Rational design, synthesis and biological evaluations of amino-noscapine: a high affinity tubulin-binding noscapinoid. J Comput Aided Mol Des 25:443-54
Santoshi, Seneha; Naik, Pradeep K; Joshi, Harish C (2011) Rational design of novel anti-microtubule agent (9-azido-noscapine) from quantitative structure activity relationship (QSAR) evaluation of noscapinoids. J Biomol Screen 16:1047-58
Aneja, Ritu; Miyagi, Tohru; Karna, Prasanthi et al. (2010) A novel microtubule-modulating agent induces mitochondrially driven caspase-dependent apoptosis via mitotic checkpoint activation in human prostate cancer cells. Eur J Cancer 46:1668-78

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