NF-kappa B may be the main gene to target in panc cancer

Discussion in 'Health and medical' started by Roger, Feb 16, 2004.

  1. Roger

    Roger Guest

    The NF-kappa B appears to be the godfather of genes involved in chemo-resistance of panc cancer
    cells. Overexpression of Bcl-XL causes resistance of panc cancer cells to chemo but Bcl-XL is
    activated by the NF-kappa B gene.

    Here's an abstract that discusses NF-kappa B.

    ------

    Annu Rev Immunol. 1996;14:649-83.

    The NF-kappa B and I kappa B proteins: new discoveries and insights.

    Baldwin AS Jr. Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill
    27599, USA.

    The transcription factor NF-kappa B has attracted widespread attention among researchers in many
    fields based on the following: its unusual and rapid regulation, the wide range of genes that it
    controls, its central role in immunological processes, the complexity of its subunits, and its
    apparent involvement in several diseases. A primary level of control for NF-kappa B is through
    interactions with an inhibitor protein called I kappa B. Recent evidence confirms the existence of
    multiple forms of I kappa B that appear to regulate NF-kappa B by distinct mechanisms. NF-kappa B
    can be activated by exposure of cells to LPS or inflammatory cytokines such as TNF or IL-1, viral
    infection or expression of certain viral gene products, UV irradiation, B or T cell activation, and
    by other physiological and nonphysiological stimuli. Activation of NF-kappa B to move into the
    nucleus is controlled by the targeted phosphorylation and subsequent degradation of I kappa B.
    Exciting new research has elaborated several important and unexpected findings that explain
    mechanisms involved in the activation of NF-kappa B. In the nucleus, NF-kappa B dimers bind to
    target DNA elements and activate transcription of genes encoding proteins involved with immune or
    inflammation responses and with cell growth control. Recent data provide evidence that NF-kappa B is
    constitutively active in several cell types, potentially playing unexpected roles in regulation of
    gene expression. In addition to advances in describing the mechanisms of NF-kappa B activation,
    excitement in NF-kappa B research has been generated by the first report of a crystal structure for
    one form of NF-kappa B, the first gene knockout studies for different forms of NF-kB and of I kappa
    B, and the implications for therapies of diseases thought to involve the inappropriate activation of
    NF-kappa B.
     
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  2. Orac

    Orac Guest

    In article <[email protected]>,
    "Roger" <[email protected]> wrote:

    > The NF-kappa B appears to be the godfather of genes involved in chemo-resistance of panc cancer
    > cells. Overexpression of Bcl-XL causes resistance of panc cancer cells to chemo but Bcl-XL is
    > activated by the NF-kappa B gene.
    >
    > Here's an abstract that discusses NF-kappa B.

    Way too simplistic, I'm afraid. NF-kB is a transcription factor that is activated by tumor necrosis
    factor-alpha and various proinflammatory stimuli, such as bacterial lipopolysaccharides. In general,
    it activates the transcription of genes associated with inflammation. True, it tends to activate
    signaling pathways associated with cell survival and has been implicatd in carcinogenesis of some
    cell types, but its specific activities tend to be cell type-specific and variable. Scientists have
    been trying to target NF-kB for years, but it is unclear how important it is in the overall process
    of carcinogenesis and chemoresistance. For example, it is not clear whether NF-kB is in and of
    itself responsible for carcinogenesis in some cell types or whether its constitutive activation is a
    result of other alterations in the cell that lead to cancer (a primary vs. secondary phenomenon).

    The reference you cite is an old one, from 1996. Way more has been discovered about NF-kB since
    then. For more recent articles (review and otherwise) culled from my reference collection, try

    Bharti AC and BB Aggarwal (2002). Nuclear factor-kappa B and cancer: its role in prevention and
    therapy. Biochem Pharmacol 64: 883-888.

    Karin M, Y Cao, FR Greten, and ZW Li (2002). NF-kappaB in cancer: from innocent bystander to major
    culprit. Nat Rev Cancer 2: 301-310.

    Karin M and A Lin (2002). NF-kappaB at the crossroads of life and death. Nat Immunol 3: 221-227.

    Senftleben U and M Karin (2002). The IKK/NF-kappaB pathway. Crit Care Med 30: S18-S26.

    Yu HG, X Zhong, YN Yang, HS Luo, JP Yu, JJ Meier, H Schrader, A Bastian, WE Schmidt, and F Schmitz
    (2003). Increased expression of nuclear factor-kappaB/RelA is correlated with tumor angiogenesis in
    human colorectal cancer. Int J Colorectal Dis.

    And, related to pancreatic cancer:

    Fujioka S, GM Sclabas, C Schmidt, J Niu, WA Frederick, QG Dong, JL Abbruzzese, DB Evans, C Baker,
    and PJ Chiao (2003). Inhibition of constitutive NF-kappa B activity by I kappa B alpha M suppresses
    tumorigenesis. Oncogene 22: 1365-1370.

    --
    Orac |"A statement of fact cannot be insolent."
    |
    |"If you cannot listen to the answers, why do you inconvenience me with questions?"
     
  3. Roger

    Roger Guest

    "Orac" <[email protected]> wrote in message
    news:eek:[email protected]...
    > In article <[email protected]>, "Roger"
    > <[email protected]> wrote:
    >
    > > The NF-kappa B appears to be the godfather of genes involved in chemo-resistance of panc cancer
    > > cells. Overexpression of Bcl-XL causes resistance of panc cancer cells to chemo but Bcl-XL is
    > > activated by the NF-kappa B gene.
    > >
    > > Here's an abstract that discusses NF-kappa B.
    >
    > Way too simplistic, I'm afraid. NF-kB is a transcription factor that is activated by tumor
    > necrosis factor-alpha and various proinflammatory stimuli, such as bacterial lipopolysaccharides.
    > In general, it activates the transcription of genes associated with inflammation.

    With ya so far.

    > True, it tends to activate signaling pathways associated with cell survival and has been implicatd
    > in carcinogenesis of some cell types, but its specific activities tend to be cell type-specific
    > and variable.

    In terms of cancer cells only, from the reading on Pubmed I've done, I've only seen bad things
    happen when it gets activated. Are you saying that in some cancer cells, activating it can be good
    (in terms of the patients health) or that some cancer cells are indifferent to it?

    > Scientists have been trying to target NF-kB for years, but it is unclear how important it is in
    > the overall process of carcinogenesis and chemoresistance. For example, it is not clear whether
    > NF-kB is in and of itself responsible for carcinogenesis in some cell types or whether its
    > constitutive activation is a result of other alterations in the cell that lead to cancer (a
    > primary vs. secondary phenomenon).

    I've read over and over again at Pubmed how it's an anti-apoptotic agent in cancer cells which is
    why it reduces the effectiveness of chemo. I posted earlier an abstract which said it was the main
    reason gemcitibane didn't work all that well in panc cancer.

    In the middle of writing this post, I just read an abstract where Taxol's effectiveness is reduced
    by inhibiting NF-kappa-B. But that appears to be the exeption to the rule (at least that's the
    impression I have from the many Pubmed abstracts I've read).

    > The reference you cite is an old one, from 1996. Way more has been discovered about NF-kB since
    > then. For more recent articles (review and otherwise) culled from my reference collection, try

    I've read a lot from this year. It appears to be a very hot area of research. It appears that anti-
    oxidants and anti-inflammatory agents are NF-kappaB inhibitors. I read a little while ago that
    vitamin C is an NF-kappaB inhibitor.

    This might explain the good results Pauling and his co-author got with cancer patients. If nothing
    else, the high doses of vitamin C would seem to lower the growth factor levels cancer cells use to
    proliferate, cause angiogenesis, and metastasize. Pauling mentioned the contradictory results the
    Mayo Clinic people got and criticized the study for using radiation and chemo on their patients, two
    agents which might reduce the effectiveness of vit C if vit c is working through reduced
    inflammation.

    Thanks for the abstracts. I'll bring up on Pubmed and read them.

    Roger

    >
    > Bharti AC and BB Aggarwal (2002). Nuclear factor-kappa B and cancer: its role in prevention and
    > therapy. Biochem Pharmacol 64: 883-888.
    >
    > Karin M, Y Cao, FR Greten, and ZW Li (2002). NF-kappaB in cancer: from innocent bystander to major
    > culprit. Nat Rev Cancer 2: 301-310.
    >
    > Karin M and A Lin (2002). NF-kappaB at the crossroads of life and death. Nat Immunol 3: 221-227.
    >
    > Senftleben U and M Karin (2002). The IKK/NF-kappaB pathway. Crit Care Med 30: S18-S26.
    >
    > Yu HG, X Zhong, YN Yang, HS Luo, JP Yu, JJ Meier, H Schrader, A Bastian, WE Schmidt, and F Schmitz
    > (2003). Increased expression of nuclear factor-kappaB/RelA is correlated with tumor angiogenesis
    > in human colorectal cancer. Int J Colorectal Dis.
    >
    > And, related to pancreatic cancer:
    >
    > Fujioka S, GM Sclabas, C Schmidt, J Niu, WA Frederick, QG Dong, JL Abbruzzese, DB Evans, C Baker,
    > and PJ Chiao (2003). Inhibition of constitutive NF-kappa B activity by I kappa B alpha M
    > suppresses tumorigenesis. Oncogene 22: 1365-1370.
    >
    > --
    > Orac |"A statement of fact cannot be insolent."
    > |
    > |"If you cannot listen to the answers, why do you inconvenience me with questions?"
     
  4. Orac

    Orac Guest

    In article <i%[email protected]>,
    "Roger" <[email protected]> wrote:

    > "Orac" <[email protected]> wrote in message news:eek:[email protected]
    > ge1.srv.hcvlny.cv.net...
    > > In article <[email protected]>, "Roger" <[email protected]>
    > > wrote:
    > >
    > > > The NF-kappa B appears to be the godfather of genes involved in chemo-resistance of panc
    > > > cancer cells. Overexpression of Bcl-XL causes resistance of panc cancer cells to chemo but Bcl-
    > > > XL is activated by the NF-kappa B gene.
    > > >
    > > > Here's an abstract that discusses NF-kappa B.
    > >
    > > Way too simplistic, I'm afraid. NF-kB is a transcription factor that is activated by tumor
    > > necrosis factor-alpha and various proinflammatory stimuli, such as bacterial
    > > lipopolysaccharides. In general, it activates the transcription of genes associated with
    > > inflammation.
    >
    > With ya so far.
    >
    >
    > > True, it tends to activate signaling pathways associated with cell survival and has been
    > > implicatd in carcinogenesis of some cell types, but its specific activities tend to be cell type-
    > > specific and variable.
    >
    > In terms of cancer cells only, from the reading on Pubmed I've done, I've only seen bad things
    > happen when it gets activated. Are you saying that in some cancer cells, activating it can be good
    > (in terms of the patients health) or that some cancer cells are indifferent to it?

    Not exactly "good" but rather secondary to the main process going on.

    > > Scientists have been trying to target NF-kB for years, but it is unclear how important it is in
    > > the overall process of carcinogenesis and chemoresistance. For example, it is not clear whether
    > > NF-kB is in and of itself responsible for carcinogenesis in some cell types or whether its
    > > constitutive activation is a result of other alterations in the cell that lead to cancer (a
    > > primary vs. secondary phenomenon).
    >
    > I've read over and over again at Pubmed how it's an anti-apoptotic agent in cancer cells which is
    > why it reduces the effectiveness of chemo. I posted earlier an abstract which said it was the main
    > reason gemcitibane didn't work all that well in panc cancer.
    >
    > In the middle of writing this post, I just read an abstract where Taxol's effectiveness is reduced
    > by inhibiting NF-kappa-B. But that appears to be the exeption to the rule (at least that's the
    > impression I have from the many Pubmed abstracts I've read).

    Again, it's cell-type specific. Researchers find different specific effects in different cell types.
    It could be the difference between breast cancer cells and pancreatic cancer cells.

    > > The reference you cite is an old one, from 1996. Way more has been discovered about NF-kB since
    > > then. For more recent articles (review and otherwise) culled from my reference collection, try
    >
    > I've read a lot from this year. It appears to be a very hot area of research.

    Indeed. In fact, almost against my will, my research is leading me to study NF-kB, which is why I've
    had to do a lot of reading of the literature over the last few months. In fact, an entire Specific
    Aim of my last grant applications proposes to study the interaction between my gene and NF-kB in
    endothelial cells during angiogenesis.

    >It appears that anti-oxidants and anti-inflammatory agents are NF-kappaB inhibitors. I read a
    >little while ago that vitamin C is an NF-kappaB inhibitor.
    >
    > This might explain the good results Pauling and his co-author got with cancer patients.

    Actually, there is no good evidence that Vitamin C improves survival from cancer--even at megadoses
    proposed by Pauling. Randomized studies have so far have not shown a survival benefit. Pauling's
    original study in the 1970's was a rather poorly designed retrospective study using controls that
    were not well matched.

    >If nothing else, the high doses of vitamin C would seem to lower the growth factor levels cancer
    >cells use to proliferate, cause angiogenesis, and metastasize. Pauling mentioned the contradictory
    >results the Mayo Clinic people got and criticized the study for using radiation and chemo on their
    >patients, two agents which might reduce the effectiveness of vit C if vit c is working through
    >reduced inflammation.

    It would be unethical not to use radiation therapy and/or chemo where appropriate in favor of an
    experimental therapy whose efficacy is unknown. In any case, the last randomized study at Mayo
    showed no difference between Vitamin C and placebo.

    > Thanks for the abstracts. I'll bring up on Pubmed and read them.

    No problem.

    --
    Orac |"A statement of fact cannot be insolent."
    |
    |"If you cannot listen to the answers, why do you inconvenience me with questions?"
     
  5. Roger

    Roger Guest

    "Orac" <[email protected]> wrote in message
    news:eek:[email protected]...
    > In article <i%[email protected]>, "Roger"
    > <[email protected]> wrote:
    >
    > > "Orac" <[email protected]> wrote in message news:eek:[email protected]
    > > ge1.srv.hcvlny.cv.net...
    > > > In article <[email protected]>, "Roger" <[email protected]>
    > > > wrote:
    > > >
    > > > > The NF-kappa B appears to be the godfather of genes involved in chemo-resistance of panc
    > > > > cancer cells. Overexpression of Bcl-XL
    causes
    > > > > resistance of panc cancer cells to chemo but Bcl-XL is activated by
    the
    > > > > NF-kappa B gene.
    > > > >
    > > > > Here's an abstract that discusses NF-kappa B.
    > > >
    > > > Way too simplistic, I'm afraid. NF-kB is a transcription factor that
    is
    > > > activated by tumor necrosis factor-alpha and various proinflammatory stimuli, such as
    > > > bacterial lipopolysaccharides. In general, it
    activates
    > > > the transcription of genes associated with inflammation.
    > >
    > > With ya so far.
    > >
    > >
    > > > True, it tends to activate signaling pathways associated with cell survival and has been
    > > > implicatd in carcinogenesis of some cell types, but its specific activities tend to be cell
    > > > type-specific and variable.
    > >
    > > In terms of cancer cells only, from the reading on Pubmed I've done,
    I've
    > > only seen bad things happen when it gets activated. Are you saying that
    in
    > > some cancer cells, activating it can be good (in terms of the patients health) or that some
    > > cancer cells are indifferent to it?
    >
    > Not exactly "good" but rather secondary to the main process going on.

    From all I've seen, it's usually the main instigator, not a passive spectator. I did see one post
    where VEGF activated it and I know it activates VEGF so there may be some cross talk between the
    different growth factors and activators.

    >
    >
    > > > Scientists have been trying to target NF-kB for years, but it is unclear how important it is
    > > > in the overall process of carcinogenesis and chemoresistance.
    For
    > > > example, it is not clear whether NF-kB is in and of itself responsible for carcinogenesis in
    > > > some cell types or whether its constitutive activation is a result of other alterations in the
    > > > cell that lead to cancer (a primary vs. secondary phenomenon).
    > >
    > > I've read over and over again at Pubmed how it's an anti-apoptotic agent
    in
    > > cancer cells which is why it reduces the effectiveness of chemo. I
    posted
    > > earlier an abstract which said it was the main reason gemcitibane didn't work all that well in
    > > panc cancer.
    > >
    > > In the middle of writing this post, I just read an abstract where
    Taxol's
    > > effectiveness is reduced by inhibiting NF-kappa-B. But that appears to
    be
    > > the exeption to the rule (at least that's the impression I have from the many Pubmed abstracts
    > > I've read).
    >
    > Again, it's cell-type specific. Researchers find different specific effects in different cell
    > types. It could be the difference between breast cancer cells and pancreatic cancer cells.
    >
    >
    > > > The reference you cite is an old one, from 1996. Way more has been discovered about NF-kB
    > > > since then. For more recent articles (review
    and
    > > > otherwise) culled from my reference collection, try
    > >
    > > I've read a lot from this year. It appears to be a very hot area of research.
    >
    > Indeed. In fact, almost against my will, my research is leading me to study NF-kB, which is why
    > I've had to do a lot of reading of the literature over the last few months. In fact, an entire
    > Specific Aim of my last grant applications proposes to study the interaction between my gene and
    > NF-kB in endothelial cells during angiogenesis.

    I think it'd be neat to study that based on how powerful this molecule appears to be. You'd be on
    the forefront of cancer research that hopefully will produce some important therapeutic results.
    Good luck.

    >
    >
    > >It appears that anti-oxidants and anti-inflammatory agents are NF-kappaB inhibitors. I read a
    > >little while ago that vitamin C is an NF-kappaB inhibitor.
    > >
    > > This might explain the good results Pauling and his co-author got with cancer patients.
    >
    > Actually, there is no good evidence that Vitamin C improves survival from cancer--even at
    > megadoses proposed by Pauling. Randomized studies have so far have not shown a survival benefit.
    > Pauling's original study in the 1970's was a rather poorly designed retrospective study using
    > controls that were not well matched.

    Pauling tried to get money from the NCI to run such a trial but the funding was rejected. It wasn't
    the perfect trial but I believe the data presented by Pauling and Cameron was real and not played
    with to support a preferred outcome because I think a scientist as great as Pauling had too much
    integrity for that. In his book, Cancer and Vitamin C, he presents good reasons why vitamin C might
    be good for cancer patients (low levels of vitamin C in cancer patients, helps the immune system,
    and other reasons). And with it inhibiting NF-kappaB, that's a powerful reason it could help.

    And it wasn't just Pauling that found it prolonged survival. Here's a study from Japan that he
    quotes in the book that I found at Pubmed:

    -----

    Int J Vitam Nutr Res Suppl. 1982;23:103-13.

    Prolongation of survival times of terminal cancer patients by administration of large doses of
    ascorbate.

    Murata A, Morishige F, Yamaguchi H.

    Clinical trials administering supplemental ascorbate to terminal cancer patients were conducted
    at two hospitals in Japan. During the period 1973-1977 there were 99 patients with terminal
    cancer at the Fukuoka Torikai Hospital. The average times of survival after the date of
    designation as terminal were 43 days for 44 low-ascorbate patients and 246 days for 55 high-
    ascorbate patients. Three of the high-ascorbate patients were still alive, their average survival
    being 1550 days, on April 1, 1980. Similar effectiveness of ascorbate was also observed at the
    Kamioka Kozan Hospital. There were 31 patients with terminal cancer during the period 1975-1979.
    The average survival times were 48 days for 19 control patients and 115 days for 6 high-ascorbate
    patients. One of the high-ascorbate patients was still alive, his survival being 215 days. In
    addition to the increase in survival times, the administration of large doses of ascorbate seemed
    to improve the quality of life.

    ------

    Those results pretty much mirror what Pauling found.

    >
    >
    > >If nothing else, the high doses of vitamin C would seem to lower the growth factor levels cancer
    > >cells use to proliferate, cause angiogenesis, and metastasize. Pauling mentioned the
    > >contradictory
    results
    > > the Mayo Clinic people got and criticized the study for using radiation
    and
    > > chemo on their patients, two agents which might reduce the effectiveness
    of
    > > vit C if vit c is working through reduced inflammation.
    >
    > It would be unethical not to use radiation therapy and/or chemo where appropriate in favor of an
    > experimental therapy whose efficacy is unknown. In any case, the last randomized study at Mayo
    > showed no difference between Vitamin C and placebo.

    It would have been nice if the 2nd study had been carried out by a team of researchers different
    from the first (and at a different hospital). I'm not saying there was bias but there's a reason for
    the team to have an interest in the study not working - and that reason is to back up the results
    they found in the earlier study. A disinterested team of researchers should have performed the
    second study.

    Roger

    >
    >
    > > Thanks for the abstracts. I'll bring up on Pubmed and read them.
    >
    > No problem.
    >
    > --
    > Orac |"A statement of fact cannot be insolent."
    > |
    > |"If you cannot listen to the answers, why do you inconvenience me with questions?"
     
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