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Development of a novel nitro-derivative of noscapine for the potential treatment of drug-resistant ovarian cancer and T-cell lymphoma.

Abstract
We have shown previously that an antitussive plant alkaloid, noscapine, binds tubulin, displays anticancer activity, and has a safe pharmacological profile in humans. Structure-function analyses pointed to a proton at position-9 of the isoquinoline ring that can be modified without compromising tubulin binding activity. Thus, many noscapine analogs with different functional moieties at position-9 were synthesized. Those analogs that kill human cancer cells resistant to other antimicrotubule agents, vincas and taxanes, were screened. Here, we present one such analog, 9-nitro-noscapine (9-nitro-nos), which binds tubulin and induces apoptosis selectively in tumor cells (ovarian and T-cell lymphoma) resistant to paclitaxel, vinblastine, and teniposide. 9-Nitro-nos treatment at doses as high as 100 microM did not affect the cell cycle profile of normal human fibroblasts. This selectivity of 9-nitro-nos for cancer cells represents a unique edge over the other available antimitotics. 9-Nitro-nos perturbs the progression of cell cycle by mitotic arrest, followed by apoptotic cell death associated with increased caspase-3 activation and appearance of terminal deoxynucleotidyl transferase dUTP nick-end labeling-positive cells. Thus, we conclude that 9-nitro-nos has great potential to be a novel therapeutic agent for ovarian and T-cell lymphoma cancers, even those that have become drug-resistant to currently available chemotherapeutic drugs.
AuthorsRitu Aneja, Surya N Vangapandu, Manu Lopus, Ramesh Chandra, Dulal Panda, Harish C Joshi
JournalMolecular pharmacology (Mol Pharmacol) Vol. 69 Issue 6 Pg. 1801-9 (Jun 2006) ISSN: 0026-895X [Print] United States
PMID16517755 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • 9-nitronoscapine
  • Antimitotic Agents
  • Antineoplastic Agents
  • Tubulin
  • Noscapine
  • CASP3 protein, human
  • Caspase 3
  • Caspases
Topics
  • Antimitotic Agents (chemical synthesis, pharmacology, therapeutic use)
  • Antineoplastic Agents (therapeutic use)
  • Apoptosis
  • Caspase 3
  • Caspases (metabolism)
  • Cell Cycle (drug effects)
  • DNA Fragmentation
  • Drug Resistance, Neoplasm
  • Enzyme Activation
  • Female
  • Humans
  • Lymphoma, T-Cell (drug therapy)
  • Noscapine (analogs & derivatives, chemical synthesis, chemistry, pharmacology, therapeutic use)
  • Ovarian Neoplasms (drug therapy)
  • Tubulin (drug effects, metabolism)

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