insufficient to rescue cells from the effect of Compound C. Instead,
inhibition of the calpain-/cathepsin-mediated cell death pathway
partially rescued the antiproliferative effect of Compound C [35],
indicating that one mechanism by which Compound C kills cancer
cells independent of AMPK is by activation of the calpain/cathepsin
pathway.6 Conclusion and Perspectives
The function of physiologically active AMPK in cancer is largely
unknown. Because AMPK inhibits biosynthetic pathways and
increases insulin sensitivity (a beneficial effect for the treatment of
type II diabetes), there has been a sustained effort to develop
AMPK activators. Unfortunately, Compound C remains the only
small molecule that has been widely used to study AMPK signaling
and various aspects of cell physiology, including cell proliferation,
survival, and migration. The use of Compound C continues despite
reports that it inhibits several other kinases with a lower Km than
AMPK. Based on clear evidence from our laboratory and others,
the use of this reagent as an AMPK inhibitor is not recommended.
Even if genetic means such as silencing RNAs are used (which by
themselves can have off-target effects), the use of Compound C to
corroborate the results from genetic experiments to prove AMPK
dependency of a cellular function is unwarranted and could
be flawed. We encourage others to include a statement in their
manuscripts that due to its proven promiscuity and
non-selectivity, Compound C was not used to test AMPK function
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200 Biplab Dasgupta and William Seibel