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Breakthroughs in natural remedies for cancers

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*Pineapple, pawpaw have anticancer effects on bile duct, prostate cancer cells
*Exercise retards development of liver condition independent of weight control
*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 disease ‘cured’ by targeting pH balance as therapeutic approach

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

German researchers have demonstrated the antitumor effects of bromelain found in pineapple (Ananas comosus) and papain, which is replete in pawpaw (Carica papaya) in human bile duct cancer (cholangiocarcinoma) cell lines.

The study was published in the International Journal of Oncology.

Cholangiocarcinoma, also known as bile duct cancer, is a type of cancer that forms in the bile ducts. Symptoms of cholangiocarcinoma may include abdominal pain, yellowish skin, weight loss, generalized itching, and fever.

Researchers from the Department of Internal Medicine at the Medical University Hospital, Tübingen, Germany noted: “Cholangiocarcinoma (CC) worldwide is the most common biliary malignancy with poor prognostic value and new systemic treatments are desirable. Plant extracts like bromelain and papain, which are cysteine proteases from the fruit pineapple and papaya, are known to have antitumor activities. Therefore, in this study for the first time we investigated the anticancer effect of bromelain and papain in intra- and extra-hepatic human CC cell lines.

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“The effect of bromelain and papain on human CC cell growth, migration, invasion and epithelial plasticity was analysed using cell proliferation, wound healing, invasion and apoptosis assay, as well as western blotting. Bromelain and papain lead to a decrease in the proliferation, invasion and migration of CC cells. Both plant extracts inhibited NFκB/AMPK signalling as well as their downstream signalling proteins such as p-AKT, p-ERK, p-Stat3. Additionally, MMP9 and other epithelial- mesenchymal-transition markers were partially found to be downregulated. Apoptosis was induced after bromelain and papain treatment.

“Interestingly, bromelain showed an overall more effective inhibition of CC as compared to papain. siRNA mediated silencing of NFκB on CC cells indicated that brome- lain and papain have cytotoxic effects on human CC cell lines and bromelain and partially papain in comparison impair tumor growth by NFκB/AMPK signalling. Especially bromelain can evolve as promising, potential therapeutic option that might open new insights for the treatment of human CC.”

Bromelain is an extract of pineapple (Ananas comosus) and contains a mixture of proteases and non-protease components. Bromelain is sold in health food stores as a nutritional supplement to promote digestion, wound healing and as an anti-inflammatory agent. Oral treatment is well tolerated and there is traditional and anecdotal evidence that bromelain has different properties. Obviously, bromelain was tested in different experimental and clinical studies and it was demonstrated that this plant food has anticancer and anti-inflammatory activities. However, the precise molecular mechanisms are not fully understood.

Papain is a sulphhydryl protease from Carica papaya latex with a powerful digestive action superior to pancreatin, or pancreatic enzymes. Papain has high concentration in the fruit, stem, leaves, fruit skin and seeds. The compound has toxic effects on plant-eating bugs, supported wound healing and the juice of ripe papaya shows anti-oxidant effect. Papain is a known ingredient of herbal medicine in different countries, but there is very limited information on the molecular targets and anticancer effects. Groundbreaking studies for both compounds as anticancer therapies for CC are lacking so far. Using a model of human CC cell lines, we investigated for the first time the antitumor activity of both bromelain and papain on CC.

Meanwhile, another study published in the journal Open Access demonstrated how Papaya black seeds have beneficial anticancer effects on PC-3 prostate cancer cells.

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The American researchers from Virginia State University, Petersburg, United States (U.S.) investigated the effect of papaya seeds on prostate cancer (PC) using PC-3 cell line because papaya seeds have effects on the male reproductive system notably decreasing sperm concentration, motility, and viability, leading to azoospermia after short-to-long-term treatment.

The black seeds from yellow (ripe) papaya and white seeds from green (unripe) papaya were harvested and then extracted in water, 80 per cent methanol, and hexane. The cytotoxic effects of seeds extracts were determined using a WST-1 proliferation assay. The amount of total polyphenols was determined using Folin Ciocalteu reagent.

The results showed the methanol extracts from black seeds significantly (P < 0.05) decreased cell proliferation of PC-3 cells whereas hexane- and water-extracts have no effect. However, the water-extract from white seeds stimulated PC cell proliferation. The black seeds contained significantly more polyphenols than that of white seeds. The data suggest that black seeds from papaya have anticancer effects on PCs whereas white seeds stimulated prostate cancer proliferation.

The anticancer effect of black seeds may be because of their high concentration of polyphenols.

The researchers concluded: “The black seeds from papaya may have a potential to reduce growth of prostate cells; however, consumption of white seeds should be avoided as they may stimulate pre-existing prostate cancer.”

Meanwhile, a new study indicates exercise can help prevent liver cancer. According to a study published in the Journal of Hepatology, exercise retards development of liver cancer by direct effects independent of weight control in an animal model that closely resembles humans with fatty liver disease.

Liver cancer is the fourth most common cause of cancer death worldwide and is growing rapidly due to the “diabesity pandemic.”

The new study reported in the Journal of Hepatology, published by Elsevier, provides strong evidence that voluntary exercise could help prevent the most common type of liver cancer, hepatocellular carcinoma, and identifies the molecular signaling pathways involved.

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Until now, fatty liver disease is common with obesity and diabetes and contributes to rapidly increasing rates of liver cancer throughout the world. More than 800,000 people worldwide are diagnosed with this cancer each year. It is also a leading cause of cancer deaths, accounting globally for more than 700,000 deaths each year.

Lead investigator Geoffrey C. Farrell, MD, Liver Research Group, ANU Medical School, Australian National University at The Canberra Hospital, Garran, ACT, Australia, said: “As yet there are very few effective therapies for liver cancer (the death rate approximates the incidence), so approaches to prevent liver cancer are greatly needed.

“Some population data suggest that persons who exercise regularly are less likely to develop liver cancer but, studies addressing whether this has a real biological basis, and, if so, identifying the molecular mechanism that produces such a protective effect, are few and the findings have been inconclusive.”

Investigators studied whether exercise reduces the development of liver cancer in obese/diabetic mice. Mice are genetically driven to eat so that they become obese and develop type 2 diabetes as young adults were injected early in life with a low dose of a cancer-causing agent. Half of the mice were allowed regular access to a running wheel; the other half were not and remained sedentary. The mice ran up to 40 kilometers a day as measured by rotations of the exercise wheel. This slowed down the weight gain for three months, but at the end of six months of experiments even the exercising mice were obese. At six months, most of the sedentary mice had liver cancer while none of the exercising mice had developed it.

This research shows that exercise can stop development of liver cancer in mice that have fatty liver disease related to obesity and type 2 diabetes. Specifically, while nearly all obese mice injected with a low dose of a cancer-causing agent developed liver cancer within six months, mice that regularly exercised failed to do so. They were completely protected against liver cancer development in the timeframe of these experiments. Weight control did not mitigate the development of liver cancer.

Investigators also carried out detailed mechanistic studies that partly clarified how exercise can prevent liver cancer. They showed that the beneficial effects of voluntary exercise were exerted via molecular signaling pathways, two of which were identified as tumor suppressor gene p53 and the stress-activated protein kinase JNK1.

The investigators first demonstrated JNK1 activation to be a key factor that can be “switched off” by exercise and proved its involvement by separate studies in obese mice lacking JNK1. They also demonstrated that activated p53, known as “guardian of the cell” and “policeman of the oncogenes,” is important for regulation of the cell cycle inhibitor, p27, thereby stopping the persistent growth of altered cells destined to become cancerous.

Dr. Farrell added: “Exercise has already been shown to improve some outcomes for patients with cirrhosis. If the present studies in an animal model that closely resembles humans with fatty liver disease can be replicated in patients, it is likely that exercise could delay onset of liver cancer and mitigate its severity, if not completely prevent it – thereby greatly improving patient outcomes.

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“Also, knowing the molecular pathways involved points to ways that drugs or pharmaconutrients could be employed to harness the powerful protective effect of exercise to lower risk of liver cancer in overweight people with diabetes.”

Meanwhile, can consuming a diet high in fibre reduce 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 fiber 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.

When the investigators pooled data from the 20 observational studies they identified, “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, emphasizing 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.

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“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 hypothesized 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 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.

Pawpaw seeds

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.”

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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.

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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.”

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