Metformin: Multi-faceted protection against cancer
Sonia Del Barco1,2,*, Alejandro Vazquez-Martin2,3,*, Sílvia Cufí2,3, Cristina Oliveras-
Ferraros2,3, Joaquim Bosch-Barrera1,2, Jorge Joven4, Begoña Martin-Castillo2,5,
Javier A. Menendez2,3
Published: December 24, 2011
The biguanide metformin, a widely used drug for the treatment of type 2 diabetes,
may exert cancer chemopreventive effects by suppressing the transformative and
hyperproliferative processes that initiate carcinogenesis. Metformin’s molecular
targets in cancer cells (e.g., mTOR, HER2) are similar to those currently being
used for directed cancer therapy. However, metformin is nontoxic and might be
extremely useful for enhancing treatment efficacy of mechanism-based and
biologically targeted drugs.
Here, we first revisit the epidemiological, preclinical,
and clinical evidence from the last 5 years showing that metformin is a promising
candidate for oncology therapeutics. Second, the anticancer effects of metformin
by both direct (insulin-independent) and indirect (insulin-dependent) mechanisms
are discussed in terms of metformin-targeted processes and the ontogenesis of
cancer stem cells (CSC), including Epithelial-to-Mesenchymal Transition (EMT) and
microRNAs-regulated dedifferentiation of CSCs.
Finally, we present preliminary
evidence that metformin may regulate cellular senescence, an innate safeguard
against cellular immortalization.
There are two main lines of evidence that suggest
that metformin’s primary target is the immortalizing step during tumorigenesis.
If metformin therapy presents an intrinsic barrier against tumorigenesis
by lowering the threshold for stress-induced senescence, metformin therapeutic
strategies may be pivotal for therapeutic intervention for cancer.
- First, metformin activates intracellular DNA damage response checkpoints.
metformin attenuates the anti-senescence effects of the ATP-generating glycolytic
metabotype-the Warburg effect-, which is required for self-renewal and proliferation
future clinical trials will elucidate whether metformin has the potential to be used
in preventive and treatment settings as an adjuvant to current cancer therapeutics.