Conclusions

If the scheme hypothesized in Fig. 7 proves correct, the obvious unanswered question are: how does the removal of polyamines result in Src activation? Could polyamines prevent the translocation of Src to the membrane? Could they block its activation site? Obviously, there are as many possibilities as there are steps in the activation process. The answers to these questions could prove interesting and important to our understanding not only of polyamine interactions, but also apoptosis itself.

Pp2a Stat3

Fig. 7. The effects of polyamine depletion (DFMO) on pathways regulating apoptosis. Activation of Src leads to the activation of transcription factors NF-kB, ERK, and STAT3. Src phosphorylates PP2A, inactivating it, which prevents it from inactivating Akt, ERK, and Bcl-2. In addition, PP2A is unable to dephosphorylate IkBa and Bad, keeping them in the inactive state. Plus and minus signs refer to the activity of the individual molecules.

Fig. 7. The effects of polyamine depletion (DFMO) on pathways regulating apoptosis. Activation of Src leads to the activation of transcription factors NF-kB, ERK, and STAT3. Src phosphorylates PP2A, inactivating it, which prevents it from inactivating Akt, ERK, and Bcl-2. In addition, PP2A is unable to dephosphorylate IkBa and Bad, keeping them in the inactive state. Plus and minus signs refer to the activity of the individual molecules.

That polyamine depletion decreases apoptosis in vivo and in vitro suggests the possibility that DFMO may have an as-yet untested use in cancer therapy. For some time, DFMO has been used as an adjunct to chemotherapy to kill cancer cells—with mixed results. One of the major limiting factors in cancer therapy is the so-called gastrointestinal syndrome caused by the therapeutic agent inducing apoptosis in the rapidly growing normal enterocytes and the cancer cells. These patients develop nausea, diarrhea, and lose weight, limiting the doses, duration, and effectiveness of their therapy. It may be possible to provide some degree of protection by administering DFMO orally to deplete these cells of polyamines before the exposure to therapeutic chemicals.

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