Fighting Prostate Cancer with Natural Products

Prostate cancer is one of the most commonly occurring cancers in the United States and remains the second-leading cause of death among men. The American Cancer Society predicts that prostate cancer will claim more than 35,000 American lives this year.¹ Advanced cases of the disease are difficult to manage because patients become increasingly unresponsive to treatment and succumb to severe side effects.

“We need to do better,” says Dr. Anait S. Levenson, head of the Cancer Research Laboratory at Long Island University, Brookville, NY. “The answer lies in effective prevention.”

Our story began decades ago when Dr. Levenson and her team first identified an important oncogenic driver of prostate cancer known as metastasis-associated protein 1 (MTA1). It was determined that MTA1 was useful not only as a prognostic marker for prostate cancer but also, more importantly, as a pharmacological target for plant-derived polyphenols known as stilbenes, found mainly in grapes and blueberries.²

Dr. Levenson and her team worked extensively with Resveratrol and Pterostilbene and were able to show that these compounds could effectively reduce the progression of prostate cancer by blocking MTA1-mediated signaling pathways.³ “Resveratrol and related polyphenols have been studied for many years and are known to have numerous health benefits, including anti-inflammatory, cardioprotective, neuroprotective, anti-ageing and anticancer effects,” explains postdoctoral cancer biologist, Dr. Gisella Campanelli, “but their clinical usefulness is limited due to extensive metabolism and low systemic bioavailability.”

Not long after, at a conference in Hawaii, Hosoda Nutritional representative, Mr. Dicky Gunawan, approached Dr. Levenson with a proposal. Inspired by her lecture on stilbene monomers, he offered Dr. Levenson a commercially unavailable stilbene compound for her to consider in her upcoming studies. It was a serendipitous chance encounter that would soon prove to be a significant step towards targeted therapy for prostate cancer. Mr. Gunawan had given Dr. Levenson Gnetin C, a resveratrol-dimer naturally present in the seeds of Gnetum gnemon (Melinjo), a plant which is commonly used in Indonesian cuisine.

Dr. Levenson’s laboratory demonstrated that, compared to Resveratrol and other related monomeric analogs, Gnetin C could more potently reduce proliferation, survival, angiogenesis, and metastatic potential of prostate cancer cells.⁴ Experiments also revealed that Gnetin C acts through potent inhibition of key molecular drivers of prostate cancer such as androgen receptor (AR) and MTA1 signaling, which are known to promote advanced metastatic prostate cancer.⁵ After in vitro experiments produced some encouraging results, the next question was whether Gnetin C could be effective in vivo.

Men whose prostate cancer risk is defined as “very low,” “low,” and “favorable intermediate” are merely monitored, but not offered any measure of treatment or prevention.⁶ Could the onset of prostate cancer in patients under “active surveillance,” who are at greater risk of developing the disease, be delayed by supplementing their diet?

In a high-risk, precancerous mouse model of prostate cancer, Dr. Levenson’s team showed that a diet supplemented with Gnetin C was associated with significantly lower tumor progression, less inflammation, and histology showing lower malignancy potential. Importantly, Gnetin C showed greater tissue accumulation, confirming better bioavailability and higher systemic exposure compared to other stilbenes.⁷ This kind of interception can protect the precancerous population of patients from developing prostate cancer.

“We are only beginning to scratch the surface,” says Dr. Levenson. “Gnetin C is a relatively new isolated compound, and laboratory studies are still in their infancy. Our published data, thus far, indicate that a Gnetin C-supplemented diet could benefit an overlooked at-risk subpopulation of patients, and if used parenterally in combinatorial regimens, Gnetin C could also block progression to metastatic disease.”

Dr. Levenson’s Cancer Research Laboratory at Long Island University is making great strides for the future of prostate cancer management. In the next phase, the Levenson Lab will explore synthetic analogs of Gnetin C targeting AR and MTA1 using AI-aided technology. Nutritional interception with Gnetin C has the potential to impact the lives of thousands of American men, sparing them from debilitating disease, invasive surgery, and aggressive treatments which are at times ineffective or accompanied by undesirable side effects.

The Levenson lab is dedicated to making impactful contributions to cancer research and pharmacology, and it is passionate about making a difference in men’s lives.

References

1. https://www.cancer.org/cancer/types/prostate-cancer/about/key-statistics.html
2. Kai L, Wang J, Ivanovic M, Chung YT, Laskin WB, Schulze-Hoepfner F, Mirochnik Y, Satcher RL, and Levenson AS (2011), “Targeting prostate cancer angiogenesis through metastasis-associated protein 1 (MTA1),” Prostate, 71 (3) (2011), pp. 268–280.
3. Levenson AS (2022), “Metastasis-associated protein 1-mediated antitumor and anticancer activity of dietary stilbenes for prostate cancer chemoprevention and therapy,” Seminars in Cancer Biology, 80:107–117.
4. Kumar A., Dholakia K., Sikorska G., Martinez LA., and Levenson AS (2019), “MTA1-dependent anticancer activity of Gnetin C in prostate cancer,” Nutrients, 11:2096.
5. Campanelli G, Deabel RA, Puaar A, Devarakonda LS, Parupathi P, Zhang J, Waxner N, Yang C, Kumar A, and Levenson AS (2023), “Molecular efficacy of Gnetin C as dual-targeted therapy for castrate-resistant prostate cancer,” Mol. Nutr. Food Res., 67:e2300479.
6. https://www.cancer.org/cancer/types/prostate-cancer/treating/by-stage.html
7. Parupathi P, Campanelli G, Deabel RA, Puaar A, Devarakonda LS, Kumar A, and Levenson AS (2022), “Gnetin C intercepts MTA1-associated neoplastic progression in prostate cancer,” Cancers, 14:6038.