Development of a novel nitro-derivative of noscapine for the potential treatment of drug-resistant ovarian cancer and T-cell lymphoma.
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.
Aneja
Ritu
R
Department of Cell Biology, Emory University School of Medicine, Laboratory for Drug Discovery and Research, 615 Michael St., Atlanta, GA 30322, USA.
Vangapandu
Surya N
SN
Lopus
Manu
M
Chandra
Ramesh
R
Panda
Dulal
D
Joshi
Harish C
HC
D050256:Antimitotic Agents / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D053938:DNA Fragmentation; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D016399:Lymphoma, T-Cell / Q000188:drug therapy*; D009665:Noscapine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D014404:Tubulin / Q000187:drug effects / Q000378:metabolism
C511618:9-nitronoscapine; D050256:Antimitotic Agents; D000970:Antineoplastic Agents; D014404:Tubulin; D009665:Noscapine; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases