Milestone in Cancer Stem Cell Research

Pao Pereira Fights Cancer Stem Cells!

New research just published in Integrative Cancer Therapies shows that the Pao pereira plant extract inhibits pancreatic cancer stem cells. This dramatic result means that the extract will be useful for preventing cancer recurrence.

Everyone knows that cancer treatments are not cancer cures. Chemotherapy treatments kill cancer cells and shrink tumors, but the cancer often comes back. Cancer stem cells (CSCs) are the culprit because they are resistant to anti-cancer drugs, they can metastasize and form new tumors. CSCs make up a small fraction of the cells in a tumor that survive after the majority of primary cancer cells are killed by anti-cancer drugs. The CSCs persist, spread and restart tumor growth.

CSCs are also referred to as cancer stem-like cells because they share the capacity for self-proliferation with normal stem cells that are involved in the renewal and repair of tissues, but unlike normal stem cells, CSCs are cancerous and drug resistant.

In vitro experiments show Pao pereira reducing the number of pancreatic CSCs (see figure below).

As the amount of Pao pereira is increased, the number of pancreatic cancer stem cells (spheroids) decrease dramatically. In additional cell-based studies, the Pao pereira extract also specifically reduced the pancreatic cancer stem cell population.

In vivo experiments showed that Pao pereira inhibited the capacity of pancreatic CSCs to form tumors – the defining characteristic of CSCs – and significantly reduce the volume of tumors that did form (see figure below).

At day 6 (Figure A), tumor formation rate in the control group reached 80%, while in Pao-treated group it was only 10%. At day 20, when the treatment stopped, all mice in control group were bearing tumors on both flanks (100% tumor formation), while the Pao-treated group only had 30% tumor formation. Growth of the formed tumors was also inhibited by Pao pereira treatment compared with the control group (Figure B). A long-term inhibitory effect in tumor growth was observed after treatment had stopped. Pao pereira works by lowering the signals that trigger the pancreatic cancer stem-like cell properties that lead to cancer recurrence.

The researchers at Kansas University Medical Center concluded that Pao pereira holds great promise as a novel treatment for targeting pancreatic CSCs, an essential component of treatments that will lead to real cancer cures.

Extract of the Medicinal Plant Pao Pereira Inhibits Pancreatic Cancer Stem-Like Cell In Vitro and In Vivo
Dong, P. Chen and Q Chen. Integrative Cancer Therapies. July 2018. doi: 10.1177/1534735418786027

Publication on the anti-cancer and anti-inflammatory activities of Pao pereira

November 2013 – 'Pao pereira Extract Suppresses Castration- Resistant Prostate Cancer Cell Growth, Survival and Invasion Through Inhibition of NFkB Signaling'

by Cunjie Chang, BS, Wei Zhao, MS, Bingxian Xie, BS, Yongming Deng, BS, Tao Han, BM, Yangyan Cui, BS, Yundong Dai, BS, Zhen Zhang, BS, Jimin Gao, MD, PhD, Hongqian Guo, MD, PhD, and Jun Yan, PhD.
Integr Cancer Ther. 2014 May;13(3):249-58. Doi: 10.1177/1534735413510557. Epub 2013 Nov 27

Nanjing_UniversityDr. Jun Yan from Dr. Aaron Katz's laboratory at Columbia University Medical Center is continuing research (University of Nanjing, China) on the anti-cancer and anti-inflammatory activities of Pao Pereira (extract provided by Natural Source International, Ltd.).

Dr. Jun Yan uses up to date techniques to determine how the Pao pereira extract exerts its effects, what molecules it influences in the cell and what responses are triggered. The publication shows that this Pao pereira extract is effective against prostate cancer cells that no longer respond to agents that interfere with hormone action.

Such drugs are specifically designed to limit the effects of testosterone, the male hormone that stimulates the growth of prostate cancer cells. Over time, prostate tumors become resistant to these anti-hormones indicting that the cancer has become more aggressive. The study shows that these hormone independent prostate cancer cells are susceptible to the growth inhibition of Pao pereira as are prostate cancers that still respond to testosterone. The study also revealed that Pao pereira acts on a signaling complex called NFkB—a control center regulating cell survival, proliferation, and invasion. The results suggest that Pao pereira will be useful for men with advanced hormone-independent prostate cancer.

Abstract

Pao pereira Extract Suppresses Castration Resistant Prostate Cancer Cell Growth

Pao extract, derived from bark of Amazonian tree Pao Pereira, is commonly used in South American medicine. A recent study showed that Pao extract repressed androgen-dependent LNCaP prostate cancer cell growth. We hypothesize that Pao extract asserts its anticancer effects on metastatic castration-resistant prostate cancer (CRPC) cells. Pao extract suppressed CRPC PC3 cell growth in a dose- and time-dependent manner, through induction of apoptosis and cell cycle arrest. Pao extract treatment induced cell cycle inhibitors, p21 and p27, and repressed PCNA, Cyclin A and Cyclin D1. Furthermore, Pao extract also induced the upregulation of pro-apoptotic Bax, reduction of anti-apoptotic Bcl-2, Bcl-xL , and XIAP expression, which were associated with the cleavage of PARP protein. Moreover, Pao extract treatment blocked PC3 cell migration and invasion. Mechanistically, Pao extract suppressed phosphorylation levels of AKT and NFκB/p65, NFκB DNA binding activity, and luciferase reporter activity. Pao inhibited TNFα-induced relocation of NFκB/p65 to the nucleus, NFκB/p65 transcription activity, and MMP9 activity as shown by zymography. Consistently, NFκB/p65 downstream targets involved in proliferation (Cyclin D1), survival (Bcl-2, Bcl-xL , and XIAP), and metastasis (VEGFa, MMP9, and GROα/CXCL1) were also downregulated by Pao extract. Finally, forced expression of NFκB/p65 reversed the growth inhibitory effect of Pao extract. Overall, Pao extract induced cell growth arrest, apoptosis, partially through inhibiting NFκB activation in prostate cancer cells. These data suggest that Pao extract may be beneficial for protection against CRPC.

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Publication on Pao pereira Extract against Pancreatic Cancer

March 2013 – 'Inhibition of Pancreatic Cancer and Potentiation of Gemcitabine Effects by the Extract of Pao Pereira'

by JUN YU, JEANNE DRISKO and QI CHEN
Oncology Reports' Journal (doi: 10.3892/or.2013.2461)

Kansas universityThe scientific team at the University of Kansas Medical Center has just published a new article entitled, 'Inhibition of Pancreatic Cancer and Potentiation of Gemcitabine Effects by the Extract of Pao Pereira' in the 'Oncology Reports' Journal (doi: 10.3892/or.2013.2461).

This scientific paper describes the results of in vitro and in vivo studies demonstrating the anti-cancer effect of the Pao pereira extract, used alone and in combination with gemcitabine (chemotherapy used in most cancer treatments), in multiple cancer cell lines including those of the pancreas resistant to anti-mitotic drugs.

Pre-clinical studies conducted with mice, both in vitro an in vivo, confirm that adding Pao Pereira to the treatment regiment reduced the concentration of Gemcitabine to produce an equitoxic effect on pancreatic cancer cells. The Pao's anti-cancer effect was seen in vivo and in vitro working alone and in conjunction with other chemotherapy treatments. Over the course of the study, the Pao pereira was seen to suppress tumor growth significantly, by up to 72%.

This confirms another study, published just a few years ago, out of Columbia University demonstrating that the two plant extracts, Pao Pereira and Rauwolfia Vomitoria, contain Beta-Carbolines with effective anti-cancer properties which inhibit cancer cell growth, even in those cells resistant to drugs used in chemotherapy. This study, specific to anti-prostate cancer activity, also substantiated that all healthy cells were not negatively affected, thus demonstrating the safety of the plant extracts prepared by the Beljanski method.

With such promising initial results, the research will continue on Pao Pereira to assess its effectiveness on other types of cancerous cells!

Abstract

Kansas - Pao - PancreasLack of effective therapy is a major problem in the treatment of pancreatic cancer. In the present study, we investigated a natural product, the extract of Pao Pereira (Pao), for its anti-pancreatic cancer effect in vitro and in vivo, either alone or in combination with the first-line chemotherapeutic drug gemcitabine (Gem). Pao induced dose-dependent apoptosis to all five tested pancreatic cancer cell lines. The combination of Pao and Gem had a synergistic effect in the inhibition of cell growth, with combination indices (CIs)

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Clinical Trial on the synergistic effects of Rauwolfia vomitoria and Pao pereira on elevated PSA

April-May 2010 – 'Two Herbal Extracts for Protecting Prostate Cell DNA – IMCJ April 2010'

by Melissa Burchill, RN, CDN – IMCJ (Integrative Medicine: A Clinician's Journal)

A clinical trial began in 2006 and enrolled some 42 patients with elevated prostate specific antigen (PSA) readings (averaging 8 to 10 on the PSA scale) and a negative biopsy a group of men that in the industrialized world numbers in the millions.

One of the primary goals of the clinical trial was to determine if the plant extracts were safe. The research team did a dose escalation trial. The trial started at two capsules but has gone much higher, and so far all doses tested have been without side effects.

'We now know that this combination of Beljanski's extracts can significantly lower PSAs in a 12-month period. Also we have had very few patients convert to prostate cancer and have found a number of patients who have had a dramatic improvement in their urinary symptoms. Men are clearly having less frequency, better streams and better flow rates. They are not getting up at night as often.

'The bottom line is that it appears our early results are reason to be very encouraged by Beljanski's extracts' ability to lower PSA and help older men urinate better, too.'

So how important are Beljanski's findings to men's health? 'There are a lot of men undergoing PSA screening,' Dr. Katz said. 'The PSA supposedly stands for 'prostate specific antigen' but I say it is more accurately 'patient stimulated anxiety.' When a man's PSA is elevated, there could be many reasons for this, having nothing to do with cancer. But what we know now is that these cells that are growing can develop into cancer, and we would like to stop them from doing so. Also if the cells keep growing even in benign fashion, they will grow around the urethra and push in on it and provoke urinary symptoms in men. That's where we want to lower the growth and division of prostate cells and that's what we think we have shown with the extracts.

Source: 'The Columbia Connection' by L.Stephen Coles, MD., Ph.D. The Doctors' prescription for healthy living

Abstract

Two Herbal extract prostateDuring his 50 years of research, biochemist and molecular biologist Mirko Beljanski, PhD, discovered 2 plant extracts that appeared to inhibit the growth of cancer cells without causing any harmful side effects. The research on these products and the preliminary indications from an ongoing clinical trial are the subject of this article. In summary, Dr Beljanski made great contributions to our understanding of basic life processes and cancer. He determined that, quite apart from the occurrence of genetic mutations of DNA, carcinogens can bind to and damage the DNA double helix, thus creating a destabilized and dysfunctional structure. Dr Beljanski associated this destabilization of the DNA with excess replication, aberrant gene expression, and increased cell multiplication, which are processes that may ultimately lead to cancer. To determine which substances cause DNA destabilization and thus can be considered carcinogenic, Dr Beljanski developed what he called the Oncotest as a way to determine the effect of a compound on the structure of DNA; compounds that enhanced either UV absorption or the level of in vitro DNA synthesis were considered to have carcinogenic properties. Through use of the Oncotest, Dr Beljanski also discovered 2 natural molecules from the tropical plants Pao pereira and Rauwolfia vomitoria that specifically recognized and bound to the damaged double helix, thus preventing the process of cell division. In vitro, these 2 natural extracts have been shown to inhibit the proliferation of a wide variety of cancer cells without affecting healthy cells. Experiments with animals confirmed these results, and preliminary work with humans has provided similar indications. Clinical studies using a combination of the pao and rauwolfia extracts have yielded encouraging preliminary results by reducing prostate-specific antigen levels in men and improving symptoms of benign prostatic hyperplasia.

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Publication on Pao Pereira Extract Against Prostate Cancer

Spring 2009 – 'β-Carboline Alkaloid-Enriched Extract from the Amazonian Rain Forest Tree Pao Pereira Suppresses Prostate Cancer Cells”

by Debra L. Bemis, PhD, Jillian L. Capodice, LAc, MS, Manisha Desai, PhD, Aaron E. Katz, MD, Ralph Buttyan, PhD – Journal of the Society for Integrative Oncology, Vol 7, No2

Columbia UniversityBark extracts from the Amazonian rain forest tree Geissospermum vellosii (pao pereira), enriched in B-carboline alkaloids have significant anticancer activities in certain preclinical models. Because of the predominance of prostate cancer as a cause of cancer-related morbidity and mortality for men of Western countries, the research team at Columbia University preclinically tested the in vitro and in vivo effects of a pao pereira extract against a prototypical human prostate cancer cell line, LNCaP. When added to cultured LNCaP cells, pao pereira extract significantly suppressed cell growth in a dose-dependent fashion and induced apoptosis. Immunodeficient mice heterotopically xenografted with LNCaP cells were gavaged daily with pao pereira extract or vehicle control over 6 weeks. Tumor growth was suppressed by up to 80% in some groups compared with tumors in vehicle-treated mice

Prostate cancer is the most frequently diagnosed malignancy in males and a leading cause of cancer deaths in men.6 Given the relatively high frequency with which prostate cancer occurs, prevention offers the most likely means to reduce the health risk to men posed by the disease. If pao pereira bark extract has tumor-suppressing activity for prostate cancer without overt toxicity, one can consider the possibility that it might be used as a preventive agent as a dietary supplement.

Abstract

b carboline prostateBark extracts from the Amazonian rain forest tree Geissospermum vellosii (pao pereira), enriched in β-carboline alkaloids have significant anticancer activities in certain preclinical models. Because of the predominance of prostate cancer as a cause of cancer-related morbidity and mortality for men of Western countries, we preclinically tested the in vitro and in vivo effects of a pao pereira extract against a prototypical human prostate cancer cell line, LNCaP. When added to cultured LNCaP cells, pao pereira extract significantly suppressed cell growth in a dose-dependent fashion and induced apoptosis. Immunodeficient mice heterotopically xenografted with LNCaP cells were gavaged daily with pao pereira extract or vehicle control over 6 weeks. Tumor growth was suppressed by up to 80% in some groups compared with tumors in vehicle-treated mice. However, we observed a striking U-shaped dose-response curve in which the highest dose tested (50 mg/kg/d) was much less effective in inducing tumor cell apoptosis and in reducing tumor cell proliferation and xenograft growth compared with lower doses (10 or 20 mg/kg/d). Although this study supports the idea that a pao pereira bark extract has activity against human prostate cancer, our in vivo results suggest that its potential effectiveness in prostate cancer treatment may be limited to a narrow dose range.

Download B-Carboline Alkaloid-Enriched Extract from the Amazonian Rain Forest Tree Pao Pereira Suppresses Prostate Cancer Cells

Publication on Pao Pereira Extract Against Ovarian Cancer

September 2013 – 'The Plant Extract of Pao Pereira Potentiates Carboplatin Effects Against Ovarian Cancer' published by Informa Healthcare USA, Inc.

Jun Yu, PhD, Qi Chen, PhD.  – ISSN 1388-0209 print/ISSN 1744-5116 –
Pharmaceutical Biology

Kansas universityRecent research conducted at the University of Kansas Medical Center shows that an herbal preparation of Pao pereira, provided by Natural Source International, Ltd. could be extremely helpful.  It concludes that 'In vivo, Pao pereira alone suppressed tumor growth by 79% and decreased volume of ascites by 55%. When Pao pereira was combined with carboplatin, tumor inhibition reached 97% and ascites was completely eradicated. Pao pereira possess potent antitumor activity and could enhance carboplatin effect, and therefore holds therapeutic potential in the treatment of ovarian cancer.'

This is a breakthrough study considering that The American Cancer Society estimates that in 2013, about 22,240 new cases of ovarian cancer will be diagnosed and 14,030 women will die of ovarian cancer in the United States. According to the data, the mortality rates for ovarian cancer have not improved in the forty years since the 'War on Cancer' was declared.

The herbal preparation of Pao pereira long been used by oncologic patients and Integrative Medicine practitioners in South America. This study investigates the anticancer effects of Pao pereira (Pao), either alone or in combination with chemotherapy drugs (carboplatin), in preclinical ovarian cancer models.

The results of the study offer a breakthrough for ovarian cancer research!

Pao pereira selectively inhibited ovarian cancer cell growth but induced apoptosis (programmed cell death) and also Pao pereira greatly enhanced chemo drug cytotoxicity.

In vivo, Pao pereira alone suppressed tumor growth by 79% and decreased volume of ascites by 55%. When Pao pereira was combined with Chimio therapy, tumor inhibition reached 97% and ascites was completely eradicated.
The researchers conclude that Pao Pereira has therapeutic potential in the treatment of ovarian cancer.

Abstract

Herbal preparation of Pao pereira [Geissospermum vellosii Allem (Apocynaceae)] has long been used by oncologic patients and Integrative Medicine practitioners in South America. However, its anticancer activities have not been systematically studied. Objective: To investigate the anticancer effects of b-carboline alkaloids-enriched extract from Pao pereira (Pao), either alone or in combination with carboplatin, in preclinical ovarian cancer models. Materials and methods: Cytotoxicity of Pao (0–800 mg/ml) against different ovarian cancer cell lines and an immortalized epithelial cell line was detected by flow cytometry, MTT assay and colony formation in soft agar. Combination of Pao and carboplatin, a primary chemotherapeutic drug for ovarian cancer, was evaluated using Chou-Talalay's methods. Mice bearing intraperitoneally spread ovarian cancer were treated with 20 or 50 mg/kg/day Pao by i.p. injection. Carboplatin at 15 mg/kg/week i.p. was compared and combined to Pao treatments. Results: Pao selectively inhibited ovarian cancer cell growth with IC50 values of 180–235 mg/ml, compared to 537 mg/ml in normal cells. Pao induced apoptosis dose- and time-dependently and completely inhibited colony formation of tumor cells in soft agar at 400 mg/ml. Pao greatly enhanced carboplatin cytotoxicity, with dose reduction (DRIs) for carboplatin at 1.2–10 fold. In vivo, Pao alone suppressed tumor growth by 79% and decreased volume of ascites by 55%. When Pao was combined with carboplatin, tumor inhibition reached 97% and ascites was completely eradicated. Discussion and conclusion: Pao possess potent antitumor activity and could enhance carboplatin effect, and therefore holds therapeutic potential in the treatment of ovarian cancer.

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