Breakthroughs in natural remedies for breast, cervical, pancreatic cancers

*Regular intake of foods rich in fibre associated with lower breast tumour risk
*Natural product derived from sponge blocks growth of malignant cervical cells
*Pancreatic tumour ‘cured’ by targeting pH balance as a therapeutic approach

Scientists have recorded major breakthroughs in their quest for a natural cure for breast, cervical and pancreatic cancers.

Can consuming a diet high in fibre reduce the incidence of breast cancer? An analysis of all relevant prospective studies published early online in CANCER, a peer-reviewed journal of the American Cancer Society (ACS), found that individuals with the highest consumption of fibre had an eight percent lower risk of breast cancer. Soluble fibre was associated with lower risks of breast cancer, and higher total fibre intake was associated with a lower risk in both premenopausal and postmenopausal women.

Because studies have generated inconsistent results regarding the potential relationship between fibre intake and breast cancer, Maryam Farvid, PhD, of the Harvard T.H. Chan School of Public Health, United States, and her colleagues searched for all relevant prospective studies published through July 2019.

The investigators pooled data from the 20 observational studies.

“Our study contributes to the evidence that lifestyle factors, such as modifiable dietary practices, may affect breast cancer risk,” said Farvid. “Our findings provide research evidence supporting the American Cancer Society dietary guidelines, emphasising the importance of a diet rich in fibre, including fruits, vegetables, and whole grains.”

Importantly, the findings do not demonstrate that dietary fibre directly reduces breast cancer risk, and a randomized clinical trial is needed to test such cause and effect.

Also, scientists at Sanford Burnham Prebys have found a new way to kill pancreatic cancer cells by disrupting their pH equilibrium. The study, published in Cancer Discovery, reports how depleting an ion transport protein lowers the pH to a point that compromises pancreatic cancer cell growth.

Pancreatic cancer cells—like all cancer cells—have a constant need for energy to support their growth and expansion. To meet these energy needs, they boost metabolic pathways that normal cells don’t use and, as a consequence, produce excess acid that needs to be expelled. Increasingly, scientists have focused on manipulating cancer cell pH as an approach to treat cancers lacking effective therapies.

An assistant professor in Sanford Burnham Prebys’ NCI-designated Cancer Center, Dr. Cosimo Commisso, said: “Our study suggests that interfering with cellular pH represents a new therapeutic avenue to treat pancreatic cancer, one of the deadliest cancers for which there is currently no effective treatment.

“We have shown that a sodium-hydrogen exchanger called NHE7 plays a significant role in pancreatic tumors, and by suppressing it, we can promote cancer cell death.”

The NHE family of sodium-hydrogen exchangers are transport proteins that regulate the internal pH of cells and their organelles such as endosomes and the Golgi apparatus. They are located in membranes and work by exchanging hydrogen ions (H+) for sodium ions (Na+) and are essential for proper cell function.

A postdoctoral fellow in Commisso’s lab and the first author of the study, Koen Galenkamp, Ph.D., said: “We hypothesised that the increased acid production that occurs in tumor cells could be harnessed as a therapeutic vulnerability, so we looked for a strategy to specifically target this.

“By mining a number of pancreatic cancer databases, we found that NHE7 levels were higher in tumors compared to the normal pancreas, and highest in the tumors of patients with the poorest prognoses.”

With this information, the research team set out to understand the role of NHE7 in pancreatic cancer cells. They found that it localizes to the Golgi where it imports hydrogen ions, creating an acidic Golgi and a corresponding alkaline cytoplasm that supports cancer cell metabolism.

Galenkamp added: “This led us to test if we could make pancreatic cells vulnerable by disabling or eliminating NHE7 to undermine the alkaline cytoplasmic pH they require to stay fit.”

Through a series of experiments in pancreatic cancer cells, the research team showed that suppressing NHE7 lowers the pH of the cell’s cytoplasm, triggering cell death. Importantly, in mice transplanted with human tumors, getting rid of NHE7 caused tumors to shrink or completely stop their growth.

Commisso said: “Pancreatic cancer is predicted to soon become the second-leading cause of cancer-related deaths in the U.S.

“Given that the five-year survival rate for people newly diagnosed is less than 10 per cent, it is crystal clear that we need better therapies—and finding new cancer targets can help us tailor treatments and possibly save the lives of many more patients.”

Commisso added: “This study illustrates the potential to target pH balance as an approach to combat pancreatic cancer. Our next step is to work with the Conrad Prebys Center for Chemical Genomics—the drug discovery facility at our Institute—to find ways to disable NHE7 and limit the Golgi’s ability to sequester acid. If successful, cancer cells would be unable to maintain the proper pH that they need to grow.”

Also, Manzamine A, a natural product derived from certain groups of sponges, can block the growth of cervical cancer cells, report researchers. Manzamine A targets a protein that is highly expressed in many cancers, including cervical cancer, and is the first reported inhibitor of this protein.

Sponges, the members of the phylum Porifera, are a basal Metazoa clade as a sister of the Diploblasts. They are multicellular organisms that have bodies full of pores and channels allowing water to circulate through them, consisting of jelly-like mesohyl sandwiched between two thin layers of cells.

A sponge found in Manado Bay, Indonesia, makes a molecule called manzamine A, which stops the growth of cervical cancer cells, according to a recent publication in the Journal of Natural Products submitted by researchers at the Medical University of South Carolina (MUSC) and their collaborators. Collaborators include students and investigators at the University of South Carolina (UofSC), College of Charleston, Gadjah Mada University in Indonesia and the University of Malaya in Malaysia.

The American Cancer Society estimates that there will be 13,800 new diagnoses of cervical cancer and 4,290 deaths in 2020. Though Pap tests and Human papillomavirus (HPV) vaccination have decreased the number of cervical cancer deaths, cervical cancer remains the fourth most common cancer in women.

The MUSC-UofSC study examined the anti-growth and cancer cell-killing effects of manzamine A in four different cervical cancer cell lines. Manzamine A stopped cervical cancer cells from growing and caused some cells to die but did not have the same effects on normal noncancerous cells.

“This is a highly exciting new application for a molecule that has earlier shown significant potential for the control of malaria and has good drug-like properties,” said Mark T. Hamann, Ph.D., the SmartState Charles and Carol Cooper Endowed Chair in Pharmacy and professor in the Department of Drug Discovery and Biomedical Sciences at MUSC. Hamann also serves as the co-senior author of the report.

“Natural products have led to the development of most of our antibiotics and anti-cancer therapies and many controls for pain,” explained Hamann.

The study’s other co-senior author, Dev Karan, Ph.D., was formerly an associate professor at UofSC before moving to the Medical College of Wisconsin, where he is an associate professor in the Department of Pathology.

In earlier work, Hamann’s group identified sponge-derived compounds effective against melanoma as well as prostate and pancreatic cancers. Manzamine A is also effective against the parasite responsible for malaria, leading to a single-dose cure in rodents.

Some analogs of this unique class of drugs are candidates for the control of COVID-19, the disease caused by the new coronavirus.

In the current report, manzamine A reduced expression levels of a protein known to be highly expressed in a number of cancers, including cervical cancer, and to contribute to poorer patient outcomes.

Computer modeling showed that manzamine A shares similar structures with known inhibitors of the protein, yet manzamine A is 10 times more potent in blocking the problematic proteins.

Several patents have been filed on manzamine A, and a startup company is in the works.

Next steps are to establish its clinical relevance, according to Hamann.

“The goal now is to make sure that it works in animals and then try to advance it into clinical applications and further development,” said Hamann.

While these molecules can be synthesized in the laboratory, Hamann doesn’t think that’s the best process.

“Most of the starting materials for lab-based synthesis are derived from petroleum,” he explained. “In contrast, sponges in their natural habitat can be successfully farmed, and unlike other forms of aquaculture, clean the environment.”

Therefore, production of these molecules from sponges growing in the environment would likely be the best source while providing opportunities for economic development in rural Indonesia.

However, the potential to find new therapeutic uses like this one for natural products hinges on species diversity, according to Hamann.

“The preservation of species diversity is extremely important, as is the diversity of the chemicals they produce and the opportunities for treating cancer that they offer,” explained Hamann. “If 50 years of climate change remains unchecked, projections are that we may lose one-third of the global species diversity. So with that will go opportunities like this.”