RT Journal Article
SR Electronic
T1 Development of a Novel Nitro-Derivative of Noscapine for the Potential Treatment of Drug-Resistant Ovarian Cancer and T-Cell Lymphoma
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1801
OP 1809
DO 10.1124/mol.105.021899
VO 69
IS 6
A1 Aneja, Ritu
A1 Vangapandu, Surya N.
A1 Lopus, Manu
A1 Chandra, Ramesh
A1 Panda, Dulal
A1 Joshi, Harish C.
YR 2006
UL http://molpharm.aspetjournals.org/content/69/6/1801.abstract
AB 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 μM 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.