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cell proliferation markers in a randomised breast cancer study; possibly the status
of insulin resistance might have had some bearing on this outcome (Bonanni et al.,
2012). Metformin has often been described as well tolerated, but one should recog-
nise that this might be because low doses employed for controlling diabetes had been
administered (Pollak, 2012). There is significant evidence that metformin sensitises
tumour cells to cytotoxic therapy. Indeed one sees considerable scope for extend-
ing the efficacy of metformin by taking into account the hormonal and growth factor
receptor status. Combination with inhibitors of growth factor receptors and inhibitors
of signalling pathways identified as being activated by AMPK seems eminently wor-
thy of pre-clinical assessment. Of immense value would be targeting CSCs, which
by available accounts are targeted by metformin/AMPK activation. Perhaps, ses-
quiterpene lactone parthenolide, putatively attributed with the ability to target CSCs,
might be worthy of pre-clinical combination with metformin. Parthelonide is a natu-
rally occurring inhibitor of NF-κB signalling. It has been shown to inhibit the IKK
kinase complex which is the core element of the NF-κB cascade (Bork et al., 1997;
Hehner et al., 1999; Kwok et al., 2001). It is also said to promote ubiquitination and
degradation of mdm2 and activate p53 (Gopal et al., 2009), two important path-
ways among those influenced by AMPK. Several studies indicate that parthelonide
might target CSCs, albeit this is subject to caveats regarding the choice of markers
and using radiation resistance for identifying CSCs often with somewhat convoluted
argumentation.
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