Therapies for colon cancer: naturally speaking

What might bitter melon, magnolia tree bark and a fruit called stone apple have in common? Therapeutic potential in colon cancer, suggests Shrikant Anant, Ph.D., associate director of Cancer Prevention for The University of Kansas Cancer Center and a firm believer in nature as “the best combinatorial chemist all around” where drug discovery is concerned.

Over the years, Dr. Anant has carved his research niche on two levels: experimenting with the anticancer activity of assorted natural compounds and zeroing in on cancer stem cells, a small group thought to play critical roles in maintaining or forming new tumors. Researchers in the field often liken cancer stem cells to queen bees: a hive collapses only if the queen is destroyed; if she isn’t, the colony readily reforms. For this reason, and because these cells resist standard therapies, Dr. Anant considers them an important therapeutic target.

The secret life of cancer stem cells

Cancer stem cells are found across a broad spectrum of cancers, and Dr. Anant is sure that they exist in colon cancer – one of his main research interests – based on their protein “fingerprint.” At the University of Oklahoma, he and Courtney Houchen, M.D., discovered that the protein DCLK-1 is a molecular marker of cancer stem cells in the colon.

A member of the kinase family, DCLK-1 influences signaling processes in cells by regulating the activity of other proteins, although its precise targets remain unknown. But “when we knocked down the gene for DCLK-1 in colon cancer cells,” Dr. Anant says, “tumor growth from those cells, in mice, was completely suppressed.”

Dysfunctional signaling is often observed in cancers, for instance, along molecular pathways manned by the proteins Notch and Hippo, which help maintain the balance between cell growth and death, and determine the fate of stem cells. In colon cancer, unruly Notch signaling – aggravated by crosstalk from Hippo pathway – is associated with tumor progression and metastasis.

All of this molecular babble probably spurs the resilience and resistance of colon cancer stem cells to chemotherapy, Dr. Anant says. It’s what he and his crew are working to reverse with help from Mother Nature.

Natural compounds show promise

Among the many natural compounds that interest Dr. Anant, three in particular are further along his investigations: marmelin, honokiol and an extract from bitter melon. 

Marmelin hails from stone apples, the fruit product of the Bael tree, an aromatic gum species native to India. The tree’s essential oil has long been used in Ayurveda, or traditional Indian medicine, to treat chronic constipation. Dr. Anant extracted marmelin from the tree’s fruit, naming it after the species’ scientific handle, Aegle marmelos. He currently holds the only NCI-funded grant exploring marmelin’s potential anticancer activity and has found that this natural compound synergizes with curcumin – the principal ingredient of turmeric – in halting the formation of colon tumors. He’s also shown that marmelin keeps uncontrolled cell signaling, driven by Notch, at bay.

Honokiol, a compound contained in the bark of magnolia trees, is a traditional Japanese and Chinese remedy for gastrointestinal disorders and closely studied since the late 1990s for its activity against melanoma. Little was known about honokiol’s potential in colon cancer, however, until Dr. Anant’s group added this compound to their research repertoire. Dharmalingam Subramaniam, Ph.D., a research assistant professor at the University of Kansas Medical Center and Dr. Anant’s protégé, discovered that honokiol specifically suppresses YAP1, a Hippo pathway protein that promotes cell proliferation and is often elevated in colon cancer.

Bitter melon lives up to its name by being among the most unpalatable of fruits unless cooked. It also has a long history of Ayurvedic use in treating Type 2 diabetes. More recently, Deep Kwatra, Ph.D., one of Dr. Anant’s postdoctoral fellows, has shown that a crude bitter melon extract renders colon cancer cells more susceptible to standard chemotherapeutic agents like doxorubicin.

“Something in this bitter melon extract occupies the attention of proteins that would otherwise pump drugs like doxorubicin out of cells,” Dr. Kwatra explains, “so more of the drug can exert its anticancer effects.” He and Dr. Anant think that charantin, a compound first purified from bitter melon in 1962 and demonstrated to be effective in lowering blood sugar levels, is the likely candidate.

Next steps

In the laboratory, Dr. Anant’s group has seen that the growth of colon cancer stem cells – readily visible to the naked eye as round pinhead-sized clumps, or spheroids – is effectively muzzled with marmelin, honokiol and bitter melon extract. They know, too, that all three natural compounds block the stem cell marker DCLK-1’s function – but, as yet, not how.

The researchers are currently pursuing derivatives, or chemically modified versions, of marmelin and honokiol with greater anticancer potency. They’re also figuring out whether charantin is, in fact, the active ingredient of interest in bitter melon. Creating capsule forms of these compounds is next on the agenda, followed by early phase clinical trials. 

Dr. Anant’s research is supported by NCI RO1 CA109269, NCI R01 CA135559, NCI R01 CA151727 and the Kansas Bioscience Authority Eminent Scholarship.

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