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.