** Sea Cucumber activates
     caspases and pro-
     apoptotic proteins

** Sea Cucumber inhibits
     anti-apoptotic proteins

** Sea Cucumber inhibits  
     the tumor suppressor,  
     PTEN

** Balancing pro- and anti-
     apoptotic proteins in
     various types of cancer

** Sea Cucumber
     antagonizes PGE2
     receptors

* Angiogenesis and RTK
   inhibition
* Topoisomerase 2alpha
   inhibition
* Caspase activation
* Inhibition of tumor
   suppressor and anti-
   apoptotic proteins
* Inhibition of PGE2
   receptors

 

Angiostop Suppresses Cancer through Multiple Pathways

Cancer thrives because of defective mechanisms that prevent cancer cells from dying and allow them to proliferate and spread.

New Research: Angiostop Induces Apoptosis through Caspases and Other Proteins

When cells are no longer needed by the body, they die a natural death in a process called apoptosis. Cancer cells, however, have a defective apoptosis mechanism which allows them to continually survive, accumulate and eventually form a tumor. In this new research, scientists have found that sea cucumber activates caspases and proteins that induce apoptosis and it also inhibits proteins that block apoptosis.

Caspases are a member of the Cysteine-aspartic acid protease family, which are proteins that directly initiate and execute the apoptosis process. In cancer, caspases are either lost or deficient so increasing their expression is one way of ensuring that cancer cell death occurs.

Research shows that sea cucumber increased expression of Caspases 3, 7, 8 and 9 and consequently triggered apoptosis in cancer cells. These caspases are expressed in several cancer cells but in this new research, sea cucumber’s effects are on the following types of cancer:

• In a new study published online in January and to be officially published in May 2016, sea cucumber was found to promote programmed cancer cell death in prostate cancer by increasing expression of Caspase 3, the major executioner of apoptosis (1). It also promoted other pro-apoptotic proteins and inhibited genes that prevent apoptosis (to be discussed later).

• In lung cancer, it activated caspase 3 and 7. It also decreased growth, angiogenesis and lymph node metastasis of lung tumor xenograft without obvious toxic side effects  (2).

• In liver cancer, sea cucumber extract stimulated the expression of caspases 3, 8 and 9. Caspase 8 and 9 activate Caspase 3 to initiate the apoptosis cascade (3).

• In pancreatic cancer, it activated Caspases 3, 7 and 9 (4).

In addition, sea cucumber also acts on other types of proteins that affect the apoptosis process. Genes like Bcl-2 and survivin are overexpressed in cancer and block the activation of caspases and therefore prevent apoptosis. Genes such as Bax and BAD, on the other hand, promote apoptosis. Studies show that sea cucumber inhibited cell proliferation and induced apoptosis by inhibiting Bcl-2 and survivin in colorectal and pancreatic cancer (4,5,6). In prostate cancer, it activated the pro-apoptotic genes, Bax and BAD (1).

 

In many types of cancers, the deficiency of caspases and pro-apoptotic genes and the overexpression of anti-apoptotic genes can give cancer cells “immortality” and also become resistant to cancer drugs. That is why either activating or inhibiting these caspases or genes is an important cancer therapy mechanism. We now know that sea cucumber (Angiostop) accomplishes the following:

• Activates Caspases 3, 7, 8, 9 and Genes Bax and BAD
• Inhibits Genes, Bcl-2 and Survivin

Table 1 lists what we know so far as the different caspases and proteins that are expressed or deficient in various types of cancers. For example, breast cancer is known to be deficient in Caspase 3, 7, 8 and 9 as well as the Bax and BAD genes. Furthermore, there is an overexpression of the genes Bcl-2 and survivin in breast cancer cells, preventing apoptosis. Similarly, Caspase 3 (and other caspases) is lacking in lung, colorectal prostate, brain, liver, endometrial cancer and melanoma. And the Bcl-2 gene is overexpressed in almost all the listed types. So we can see that Angiostop has applications in all these types of cancers listed.

New Research: Sea Cucumber Activates PTEN, a Tumor Suppressor

In the prostate cancer study, sea cucumber also activated the protein Phosphatase and tensin homolog (PTEN) (1). PTEN is a tumor suppressor gene that is lost in many types of cancers and causes cell proliferation. Studies show that about 70% of prostate cancer patients have lost PTEN at diagnosis. It is also deficient in breast, lung, brain, kidney, pancreatic and endometrial cancer (Table 1). Indirectly, the loss of PTEN also affects apoptosis because that can inhibit the Akt growth factor signaling pathway that leads to caspase activation (see Figure 1).

In a 2012 National Institutes of Health (NIH)-grant supported study at the University of Maryland Greenebaum Cancer Center, sea cucumber was found to reduce the risk of metastasis by targeting Prostaglandin E2 (PGE2) signaling. Breast malignancies have elevated levels of the COX2 enzyme which leads to high levels of PGE2 and contributes to tumor growth and metastasis by acting on PGE receptors, EP2 and EP4. Studies show that sea cucumber antagonizes EP2 and EP4 receptors in breast tumors thereby inhibiting spontaneous tumor metastasis to the lungs (7).

PGE2 overexpression is not only found in breast cancer but also in lung, colorectal, prostate cancer and melanoma. So sea cucumber has potential applications in these types as well.

Inhibiting PGE2 signaling can also indirectly reduce the expression of VEGF and FGF – growth factors that promote angiogenesis (Figure 1). So this could also partly explain why sea cucumber can reduce metastasis.

Cancer cells have many factors that are viable targets of cancer therapy, as we have seen through the studies above. Angiostop (sea cucumber) addresses these factors and suppresses cancer through different mechanisms (Table 2).

For decades, we have known that Angiostop naturally inhibits angiogenesis and tyrosine kinase receptors (RTKs) such as VEGFR, EGFR, PDGFR and FGFR as well as the associated downstream signals, Akt, FAK, Paxillin and ERK (8-10). Because of its wide range of growth factor targets, it can effectively block new blood vessel growth from tumors and eventually cause them to shrink. Moreover, angiogenesis inhibitors are recommended before and after surgery in order to minimize spread and recurrence. So taking Angiostop before any invasive procedure (biopsy, surgery, colonoscopy, endoscopy, etc.) is recommended.

Angiostop is also a topoisomerase 2alpha inhibitor, attacking cancer at the DNA level in order to induce apoptosis. Since it binds with Topo 2alpha via single bond (as opposed to double bond in some chemotherapy agents), it has no toxic effects compared to Topo 2alpha inhibitor chemotherapy drugs like Adriamycin or Vincristine.

The new research on Angiostop’s action on caspases and other proteins makes it an even more attractive natural cancer therapy. By activating caspases and other proteins to promote cancer cell death and inhibiting proteins that block apoptosis, it can further reduce cell proliferation, tumor growth and metastasis.

Putting all these together, you can see how Angiostop attacks cancer through different pathways ( Please refer to Figure 1 above): the Tyrosine Kinase or RTK pathway (blue), the Apoptosis/Caspase pathway (red), the Prostaglandin E2 or PGE2 pathway (orange) and the tumor suppressor pathway (green). As you will see, each pathway is connected to each other, leading to better suppression of cancer.

When tyrosine kinases or growth factors trigger the RTK cascade, they lead to cell proliferation, cell migration and angiogenesis. For example, when EGF binds to EGFR, it triggers the FAK-Paxillin pathway that leads to cell migration and angiogenesis. Similarly, it can also trigger the Ras-Raf-MEK-MAPK-ERK pathway that leads to gene regulation, cell proliferation and eventually angiogenesis. Angiostop (seen as pink in Figure 1) inhibits many of these signals (EGFR, FAX, Paxillin, and ERK) leading to angiogenesis inhibition and tumor suppression. But the RTK pathway itself also contributes to the caspase, PGE2 and tumor suppressor pathways.

In the caspase pathway, you can see that the genes BAD and Bax promote caspase 9 activation that leads to apoptosis. But Bcl-2 and survivin inhibit caspase activation. Studies show that Angiostop does activate BAD and Bax as well as the different caspases and inhibits Bcl-2 and survivin. Growth factors can have an indirect effect on caspases as well.

When VEGF binds to VEGFR, it can trigger PI3K-AKT signaling in the RTK pathway. Akt acts on the BAD gene, which is the link between the RTK pathway and apoptosis (caspase) pathway. We know that BAD promotes apoptosis. But increased Akt expression inhibits BAD, so by blocking Akt, Angiostop can help promote apoptosis by allowing BAD to trigger caspase activation. Moreover, Angiostop inhibits ERK signaling in the nucleus so that it blocks Bcl-2 from preventing apoptosis.

Akt signaling also affects PGE2 and promotes the PTEN tumor suppressor. Specifically, it promotes COX-2 expression which then promotes PGE2 expression that leads to cell proliferation and angiogenesis. Increased PGE2 expression can also contribute to increased expression of growth factors EGF, FGF and VEGF through the EP2 and EP4 receptors. But Angiostop interrupts this positive feedback loop through two ways: it inhibits the growth factors from binding to their receptors and it antagonizes the EP2 and EP4 receptors.

So it is easy to see why Angiostop has been so effective for many cancer patients. Attacking cancer through different pathways leads to more effective results.

SUMMARY

Cancer has so many factors to it that all of them need to be addressed in order to fully manage it. We have seen that Angiostop accomplishes many of these tasks. RTK inhibition is important for suppressing cell proliferation, cell migration, angiogenesis and apoptosis. Caspase activation is essential for allowing programmed cancer cell death to occur. Activating tumor suppressors like PTEN that are absent or lacking in many types of cancers is also needed. Attacking cancer by antagonizing receptors of inflammatory factors like PGE2 is also a viable mechanism that leads to reduced cell proliferation and angiogenesis inhibition.

Many cancer patients develop resistance to chemotherapy or oral cancer drugs. Or their cancer recurs after a time. The most likely reason behind that is their cancer was not fully suppressed in the first place because most therapies attack cancer through a single pathway. Taking Angiostop or adding Angiostop to their current cancer regimen can be a more effective approach to fully suppressing cancer. Other supplements like Reishi Spore Extract, Revivin, Asparagus Extract and Myomin may also be taken for even better results.

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