How we learned the poppy kills cancer

Poppy-purple

Let’s take a little break from hypotheses and conclusions to take a look into how drugs are discovered. I’ve had the pleasure of meeting Dr. Harish C. Joshi at Emory University (Atlanta, GA) who discovered a promising drug for chemo-prevention.

For a long time (Tew et al. published in 1983) we’ve used microtubule-interacting drugs to treat cancer. Since cancer tumors grow quickly, and microtubules are protein building blocks essential to cellular division, it follows that interfering with microtubules can hurt growing tumors more than it will hurt non-cancer cells. As testament to this, the USFDA has approved use vinca alkaloids and taxanes (both microtubule drugs) for first line chemotherapy against ovarian and breast cancer.

Structure of Vincristine, a vinca alkaloid

Structure of Vincristine, a vinca alkaloid

Though these microtubule drugs are unquestionably effective, they exert too strong an effect on microtubules and subsequently have crippling side effects. Healthy cells that rely on microtubules such as neurons and hair follicles are disrupted by vinca alkaloids and taxanes, resulting in (familiar) side effects such hair loss and loss of sensation in peripheral limbs.

Structure of colchicine, a microtubule poison

Structure of colchicine, a microtubule poison

In 1998 Dr. Joshi and colleagues at Emory University looked for effective microtubule drugs with fewer side effects. They perused the Merck Index, a dictionary of chemical structures, and noted every compound that remotely resembled microtubule poisons such as colchicine and podophyllotoxin. After screening numerous compounds for anticancer activity, they found that noscapine, an extract from the opium plant used routinely as cough medicine, was a promising candidate.

Structure of noscapine, extracted from the poppy plant

Structure of noscapine, extracted from the poppy plant

Subsequent in vitro (drug testing on cancer cell lines) tests on the NIH (National Institute of Health) panel of tumor cells showed noscapine was effective against a number of cancer types. Further testing using tumors implanted in rats showed that noscapine retained antitumor activity against tumors resistant to drugs including vinca alkaloids and taxanes. Notably noscapine was equally effective against the MDR (multi-drug resistance) phenotype, cancer cells that typically do not respond to chemotherapy.

Clinical testing findings on noscapine's effects on microtubules

Clinical testing findings on noscapine’s effects on microtubules

Phase I testing (human tests) and in vivo tests using rats showed that noscapine has little to know toxicity, not surprising since it has been used for decades as cough medicine. Toxicity is hard to quantify, since at high enough of a dose seemingly benign substances such as water and sugar result in side effects. Nonetheless noscapine did not result in any of the side effects typically associated with chemotherapy.

Phase I

Currently Dr. Joshi’s lab at Emory as well as labs in England, Austrailia, China, and India are studying noscapine and noscapine derivatives for use in chemotherapy. Surprisingly there is growing evidence that noscapine is an effective treatment for stroke patients.

Source 1, 2, 3, 4, 5

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