Microtubules, leukemia, and cough syrup

Steven Heidemann

Comment on Aneja et al, page 2486

In this issue of Blood, Aneja and colleagues continue their interesting work on a novel class of antimicrotubule, anticancer, opioid drugs by showing that a synthetic derivative shows promise for leukemia treatment.

The natural opioid is noscapine, used for decades almost exclusively as an antitussive, and which even now may have new applications as cough syrup.1 Joshi's group has shown that noscapine and derivatives have interesting antimicrotubule properties that differ from the other 2 principal classes of anti-cancer drugs that target microtubules. Vinca alkaloids (eg, vinblastine) and taxanes (eg, paclitaxel [Taxol]) are widely used chemotherapeutic agents. But both are relatively toxic at effective doses, killing other dividing cells, including normal blood cells, and damaging peripheral axons, which are tightly packed with microtubules. Development of peripheral neuropathy is an important factor limiting vinca and taxane dosing.2 Further, leukemic cells often become resistant to these drugs via the multidrug resistance (MDR) phenotype.3 Aneja and colleagues now report that a more effective, brominated derivative of noscapine, EM011, shows promise as a good anticancer chemotherapy while improving on some of the limitations of the other antimicrotubule-acting drugs.

Antimicrotubule chemotherapeutic drugs exert their effect on leukemic and other rapidly proliferating cells by disrupting microtubule assembly and disassembly and thus mitosis, which in turn engages the cell-cycle mitotic checkpoint, leading to apoptosis.4 Vinca alkaloids cause extensive disassembly of microtubules, while taxanes stabilize microtubules and drive excess assembly. This wholesale disruption of microtubule dynamics engages apoptotic mechanisms in both healthy and transformed cells, leading to the toxic effect on the gut, hair, and normal hematopoietic cells. Noscapine and EM011 have a less severe impact on microtubule arrays. This class of drugs slows the normal, rhumba-like dance of microtubule assembly and disassembly (called “dynamic instability”) seen in the mitotic spindle. Aneja and colleagues find unusually specific killing of T-lymphoid but not normal cells. Further, treated mice show tumor shrinkage and increased lifespan without damage to normal blood chemistry. They postulate that EM011's “kinder, gentler” effect on microtubule dynamics and noncancer cells exploits intact checkpoints in healthy cells. These engage the mitotic checkpoint but, with healthy repair mechanisms, only arrest without leading to massive apoptosis. Such healthy cells recover a normal cell cycle after the drug is cleared from the system by metabolic degradation and secretion. In contrast, the leukemic cells, with their debilitated cell-cycle machinery, engage the apoptotic machinery right away because not only is microtubule assembly dicey, but there are other wobbly steps as well.

“Kinder, gentler” also applies to neuropathies, which result in part from the neurotoxic detergent-adjuvant used to administer insoluble taxanes and vincas, while noscapine has been administered orally for years, as it is by Aneja and colleagues. Noscapine is also likely to be less neurotoxic because it only increases the pause time between assembly and disassembly events, unlikely to have much effect on the already stable microtubule “tracks” of axonal transport. In contrast, vincas and taxanes rip up or rapidly add microtubule “tracks,” leading to a transport wreck. More generally, the long use of noscapine as an antitussive indicates it is well tolerated.

Finally, resistance to taxanes and vincas are both mediated by the P-glycoprotein drug efflux transporter encoded by the MDR1 gene, whose expression is both common and associated with poor prognosis in leukemias.3,5 Aneja and colleagues show that MDR lymphoblastoid cells show only very slightly lower levels of apoptosis than parent, non-MDR cells throughout the dosage range of EM011, and so appear to be less susceptible than other antimicrotubules to efflux.

Noscapine is from opium, that famously soothing, kinder and gentler alkaloid whose components and derivatives treat everything from pain to cough. One can hope that chemistry based on Papaver somniferum may yield yet another powerful, well-tolerated drug, this time for a true scourge of this age, cancer. ▪