Apoptosis

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Med Hypotheses 1998 May;50(5):423-33

Selenium, calcium channel blockers, and cancer risk--the Yin and Yang of apoptosis? McCarty MF Nutrition 21, San Diego, CA 92109, USA.It is increasingly clear that apoptosis plays a crucial role in the promotional phase of cancer development. Initiated pre-neoplastic clones in rat liver experience a high rate of apoptosis, and this rate has an important impact on the survival and growth of these clones. Suppression of apoptosis appears to be a universal property of cancer promoters, suggesting conversely that agents which inhibit cancer induction during the promotional phase increase the rate of apoptosis in initiated cells. Modulation of apoptosis is a likely explanation for recent striking evidence that use of calcium channel blockers substantially increases, whereas supplemental selenium substantially decreases, human cancer incidence. Non-genotoxic measures which are likely to upregulate apoptosis in pre-neoplastic/neoplastic cells--and thus may be useful in prevention and/or therapy--include selenium, retinoids/carotenoids, green tea polyphenols, caloric restriction, downregulation of IGF-I activity, high-dose tamoxifen and other protein kinase C antagonists, withdrawal or blockade of trophic hormones, isoflavones, limonene, vitamin D and cholecalciferol analogs, dietary fiber/sodium butyrate, hyperthermia, benzaldehyde derivatives, and creatine.

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what would happen if we took lots of rutuximad and 2 to 3grams of resveratrolyikes stripes and some myacin or golden seal too bootFrom: Ellen Diamond <e.diamond@...> Sent: Tuesday, September 1, 2009 5:15:43 PMSubject: apoptosis

I'm wondering if someone can explain to me, in terms that I'll hopefully be able to follow, the following:Many drugs showing promise in the field of CLL are those that make leukemia cells more receptive to apoptosis. The apoptosis, however, is still most effectively accomplished with chemo drugs like fludarabine). What’s actually going on here? Why does chemo succeed with apoptosis where other drugs such as rituxan, genasense, campath, ofatumumab, revlamid, etc. are successful only in preparing the cells for it? What's needed for these kinds of drugs or others to cross over into the apoptosis territory?-Ellen D.------------------------------------

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Dr. Furman:

Thank you for this clear explanation of a complex process.

Stein

Re: apoptosis

Ellen,

Apoptosis is a term that is often over used. Apopotosis technically means "programmed cell death". This is when the cell dies secondary to internal signals that set off a series of reactions that lead to the cell dying. The alternative to apoptosis is when the cell is damaged by physical or chemical means.

With chemotherapy, most alter the cells ability to replicate the DNA. When this happens, the cell commits suicide because it is concerned that it might make mistakes in its replication. During the life cyle of a cell, there are many proteins that help keep cells alive, like bcl-2 and NF-kappaB. These proteins help to keep the cell alive when it is damaged, in order to give it a chance to repair itself. In their absence, a cell will still be alive, but would just be more prone to damage and dying. The "apoptosis" signal would be delivered by something like chemotherapy. That is why agents like Genasense, which inhibit bcl-2, would be paired with chemotherapy.

But in cancer biology, this pairing is not always necessary. Most cancer cells are "pushing the envelope" in terms of their survival. They are living under conditions that would kill normal cells. For CLL cells, one possible thought is that the cells are able to live without help from T cells because they have such high levels of bcl-2. Inhibiting bcl-2 with ABT-263, for instance, does induce the cells to undergo apoptosis, even without chemotherapy. Here, the cells were staying alive without necessary nuturing signals because of high levels of bcl-2. With the bcl-2 turned off, and the nuturing signals not present, the cells die.

But we do know that bcl-2 helps cells resist chemotherapy, so the combination is also particularly effective.

Thus, the agents you listed do work via both paths. Ofatumumab, genasense, and Campath can induce apoptosis by themselves. For an agent like ofatumumab and Campath, the antibody activates a protein called complement which punches holes in the cell membrane. When enough proteins leak out of the cells, the cell turns on its apoptosis machinery.

Rick Furman, MD

>

> I'm wondering if someone can explain to me, in terms that I'll

> hopefully be able to follow, the following:

>

> Many drugs showing promise in the field of CLL are those that make

> leukemia cells more receptive to apoptosis. The apoptosis, however, is

> still most effectively accomplished with chemo drugs like fludarabine).

> What's actually going on here? Why does chemo succeed with apoptosis

> where other drugs such as rituxan, genasense, campath, ofatumumab,

> revlamid, etc. are successful only in preparing the cells for it?

> What's needed for these kinds of drugs or others to cross over into the

> apoptosis territory?

> -Ellen D.

>