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 M 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.

Anticancer Activity of Papaver Somniferum

“…Our findings showed that opium extracts caused high antiproliferative and low cytotoxic activities towards cell lines at IC50 concentrations; indicating they have significant potential as a useful medicine. Previous studies reported that these extracts have a similar effect with current chemotherapeutics in various cell lines [20,21]. These extracts induced decrease in cell growth in culture through causing cell shrinkage and changing their astrocyte-like and fibroblast-like structures to globular shape.…”

Methyl 2-{[(6S*,7R*,8S*)-7-acetyl-8-(4-chlorophenyl)-4-cyano-6-hydroxy-1,6-dimethyl-5,6,7,8-tetrahydroisoquinolin-3-yl]sulfanyl}acetate

“…Berberrubine, a protoberberine alkaloid, exhibits anti-tumor activity in animal models (Kim et al, 1998). It has also been reported that noscapine, a plant alkaloid, binds to tubulin and induces apoptosis selectively in tumor cells to display anti-cancer activity in ovarian and T-cell lymphoma cancers (Aneja et al, 2006). These examples demonstrate the utility of the tetrahydroisoquinoline core and why these types of compounds are of great interest.…”

Human serum albumin nanoparticles as an efficient noscapine drug delivery system for potential use in breast cancer: preparation and in vitro analysis

“…[8][9][10] It was recently reported that noscapine was effective in reducing the growth of lymphoma and increasing the survival of tumorbearing mice when administered in their drinking water. 7,[11][12][13][14][15] However, current drug delivery methods of high concentration of noscapine are inadequate.…”