Metformin could be an option to up-regulate glycolysis.

Cheers, Christian

Article Buzzai M, Jones RG, Amaravadi RK, Lum JJ, DeBerardinis RJ, Z...

Complex I inhibitors are a good choice to induce glycolysis. You can use metformin/phenformin/rotenone but you can prefer to use metformin instead of other two because it is a reversible and week inhibitor of Complex I thus will not affect cell viability as compared to other two drugs. 

Mitochondrial poisons will increase aerobic and anaerobic glycolisis:

Mitochondrial poisons

 Atovaquone is an antimalarial drug used for the treatment of pneumocystis pneumonia and toxoplasmosis and is FDA approved. At the molecular level it is a potent and selective inhibitor of OXPHOS by targeting mitochondrial complex III, inducing aerobic glycolysis and oxidative stress in cancer stem cells[i], [ii].  Atovaquone decreases the pyrimidine synthetic pathway in P falciparum dependent on mitochondria[iii].

Metformin is the most widely prescribed drug for the treatment of diabetes. Its main mechanism of action is inhibition of mitochondrial complex I, increasing the glycolytic pathway through reduction of OXPHOS. Due to lower production of mitochondrial ATP, the AMP/ATP index increases and activates AMPK which further inhibits mTOR[iv]. Used at high doses it may produce lactic acidosis due to increased lactic acid production.

Phenformin is metformin’s predecessor with similar effects on lactic acid production, but is a more powerful inhibitor of the mitochondrial respiratory chain which entails an increased risk of lactic acidosis. This adverse effect led to the withdrawal of this drug from the market[v],[vi],[vii] .  As the effect we are looking for, is precisely a strong inhibition of lactate oxidation, phenformin may be more appropriate for this purpose than metformin although it is more toxic. Regarding cancer cytotoxicity, phenformin also seems to be more powerful than metformin[viii].

Doxycycline is an antibiotic that exerts inhibition of mitochondrial protein synthesis and reduces mitochondrial complex I activity[ix], [x], [xi], [xii].

All four pharmaceuticals described as mitochondrial poisons have in common their inhibitory activity on OXPHOS and increase in lactic acid production through increased aerobic glycolysis.

Metformin, phenformin and doxycycline are weak inhibitors of mitochondrial complex I and with no effect on the rest of the mitochondrial complexes[xiii], so for a more potent inhibition of the OXPHOS process it would be convenient to associate atovaquone as  an inhibitor of complex III and possible synergistic activity with biguanides. This needs experimental testing.

[i] Fiorillo M, Lamb B, Tanowitz HB et al. Repurposing atovaquone: targeting mitocondrial complex III and OXPHOS to eradicate cancer stem cells. Oncotarget 2016; doi: 10.18632/oncotarget.9122

http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=9122&path%5B%5D=27797

[ii] Fry M, Pudney M. . Site of action of the antimalarial hydroxynaphthoquinone, 2-[trans-4-(4′-chlorophenyl) cyclohexyl]-3-hydroxy-1,4-naphthoquinone (566C80). Biochem Pharmacol 1992;43:1545-3. http://www.ncbi.nlm.nih.gov/pubmed/1314606?dopt=Abstract

[iii] Hammond DJ, Burchell JR, Pudney M.  Inhibition of pyrimidine biosynthesis de novo in Plasmodium falciparum by 2-(4-t-butylcyclohexyl)-3-hydroxy-1,4-naphthoquinone in vitro. Mol Biochem Parasitol 1985;14:97-109. http://www.ncbi.nlm.nih.gov/pubmed/3885032?dopt=Abstract

[iv] Zakikhani M, Dowling R, Fantus IG, Sonenberg N, Pollak M. Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells. Cancer Res. 2006 Nov 1;66(21):10269-73. Epub 2006 Oct 23

http://cancerres.aacrjournals.org/content/66/21/10269.full.pdf+html

[v] Stumvoll, M., Nurjhan, N., Perriello, G., Dailey, G. & Gerich, J. E. Metabolic effects of metformin in non-insulin-dependent diabetes mellitus. N. Engl. J. Med.1995; 333:550–554.

http://www.nejm.org/doi/full/10.1056/NEJM199508313330903

[vi] Pernicova I, Korbnits M. Metformin mode of action and clinical implications for diabetes and cancer. Nature Reviews Endocrinlogy 2014;10:143-156. http://www.nature.com/nrendo/journal/v10/n3/full/nrendo.2013.256.html#ref25

[vii] Janzer A, German NJ, Gonzalez Herrera KN, Asara JM, Haigis MC, Struhl K. Metformin and phenphormin deplete tricarboxylic acid cycle and glycolytic intermediates during cell transformation and NTPs in cancer stem cells. PNAS 2014; 111(29): 10574-10579. http://www.pnas.org/content/111/29/10574

[viii] Miskimins WK, Ahn HJ, Kim JY, Ryu S, Jung Y-S, Choi JY (2014) Synergistic Anti-Cancer Effect of Phenformin and Oxamate. PLoS ONE 9(1): e85576. doi:10.1371/journal.pone.0085576. http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0085576

[ix] Du Buy HG, Showacre JL. Selective localization of tetracycline in mitochondria of living cells. Science. 1961 Jan 20;133(3447):196-7. http://www.ncbi.nlm.nih.gov/pubmed/13724526

[x] Journey LJ and Goldstein MN. The effect of terramycin on the fine structure of HELa cell mitochondria. Cancer Research. 1963;23:551-554. http://cancerres.aacrjournals.org/content/23/4_Part_1/551.long

[xi] de Vries H, Kroon AM. On the effect of chloramphenicol and oxytetracycline on the biogenesis of mammalian mitochondria. Biochim Biophys Acta. 1970 Apr 15;204(2):531-41http://www.ncbi.nlm.nih.gov/pubmed/4315017

[xii] de Vries H, Arendzen AJ, Kroon AM. The interference of the macrolide antibiotics with mitochondrial protein synthesis. Biochim Biophys Acta. 1973 Dec 7;331(2):264-75.

[xiii] Bridges HR, Jones AJY, Pollak MN, Hirst J. Effects of metformin and other biguanides on oxidative phosphorylation in mitochondria. Biochem J, 2014;462:475-487. http://www.biochemj.org/content/ppbiochemj/462/3/475.full.pdf