Syrosingopine (O-carbethoxysyringoyl methylreserpate; SU-3118), a drug derived from reserpine* which was originally developed by Ciba (now Novartis) for the treatment of hypertension in 1958, in combination with the widely used diabetes drug metformin, an oral antidiabetic of the biguanide class, killed tumor cells in blood samples from leukemia patients, while it did not damage blood cells in samples from healthy patients. The combination also reduced or eliminated tumors in mice with malignant liver cancer. 
The benefit of the drug combination was discovered by researchers from the University of Basel’s Biozentrum two years ago. In a follow-up study, supported by the Swiss National Science Foundation, the Louis-Jeantet Foundation, the European Research Council (MERiC), and the Canton of Basel and recently published in Cell Reports, the scientists report that this drug cocktail induces cancer cell death by switching off their energy supply.
In addition to reducing blood glucose levels, Metformin, commonly used in the treatment of type 2 diabetes (T2DM), also has an anti-cancer effect. However, the metformin dose , is too low to inhibit cancer growth.
Metformin lowers blood glucose levels and, as a result, glucose availability to glucose-hungry cancer cells. At the cellular level, metformin inhibits mitochondrial respiration in cancer cells that are already experiencing a shortfall in glucose uptake, leading to lower adenosine 5?-triphosphate (ATP) levels. The resulting activation of AMPK leads to inhibition of mammalian target of rapamycin complex 1 (mTORC1), a major signaling hub for cell growth, translation, and metabolism. 
The previous study by Michael N. Hall, Ph.D, at the University of Basel’s Biozentrum revealed that the antihypertensive drug syrosingopine enhances metformin’s anti-cancer efficacy.
In the follow-up study, jointly performed at the Biozentrum and Basilea Pharmaceutica International, the scientists shed light on this phenomenon: The combination of the two drugs blocks a critical step in energy production thus leading to an energy shortage, which finally drives cancer cells to “suicide”.
Crippling sophisticated machinery
Cancer cells have high energy demands due to their increased metabolic needs and rapid growth. A limiting factor in meeting this demand is the molecule NAD+, which is key for the conversion of nutrients into energy.
“In order to keep the energy-generating machinery running, NAD+ must be continuously generated from NADH,” explains Don Benjamin, first author of the study.
“Interestingly, both metformin and syrosingopine prevent the regeneration of NAD+, but in two different ways,” Benjamin added.
Mode of action
Syrosingopine binds to the glycolytic enzyme ?-enolase in vitro. Furthermore, the expression of the ?-enolase isoform correlates with nonresponsiveness to the drug combination. Syrosingopine sensitized cancer cells to metformin and its more potent derivative phenformin far below the individual toxic threshold of each compound. 
Interestingly, many tumor cells shift their metabolism toward glycolysis, which means that they generate energy mainly via the breakdown of glucose to lactate. Since the accumulation of lactate leads to a blockade of the glycolytic pathway, cancer cells eliminate lactate by exporting it from the cell via specific transporters.
“We have now discovered that syrosingopine efficiently blocks the two most important lactate transporters and thus, inhibits lactate export,” Benjamin noted.
“High intracellular lactate concentrations, in turn, prevent NADH from being recycled into NAD+,” he said.
Because the anti-diabetes drug metformin blocks the second of the two cellular pathways for NAD+ regeneration, combined metformin-syrosingopine treatment results in complete loss of the cell’s NAD+ recycling capacity. The depletion of NAD+ in turn leads to cell death, as the cancer cells are no longer able to produce sufficient energy. Thus, pharmacological inhibition of lactate transporters by syrosingopine or other similarly acting drugs can increase the anti-cancer efficacy of metformin and may prove a promising approach to fighting cancer.
The identification of syrosingopine as a dual inhibitor of the two main lactate transporters is an important discovery, as currently there is no pharmacological inhibitor available for? monocarboxylate transporters 1 (MCT1) and/or 4 (MCT4).? The potential application of syrosingopine in cancer therapy could trigger a second career for this old drug.
 Blackman JG, Campion DS, Fastier FN, Mechanism of action of reserpine in producing gastric haemorrhage and erosion in the mouse Br J Pharmacol Chemother. 1959 Mar; 14(1): 112?116.
 Benjamin D, Colombi M, Hindupur SK, Betz C, Lane HA, El-Shemerly MY, Lu M, Quagliata L, et al. Syrosingopine sensitizes cancer cells to killing by metformin. Sci Adv. 2016 Dec 23;2(12):e1601756.doi: 10.1126/sciadv.1601756. eCollection 2016 Dec.
 Benjamin D, Robay D, Hindupur SK, Pohlmann J, Colombi M, El-Shemerly MY, Maira SM, Moroni C, Lane HA, Hall MN. Dual Inhibition of the Lactate Transporters MCT1 and MCT4 Is Synthetic Lethal with Metformin due to NAD+ Depletion in Cancer Cells. Cell Rep. 2018 Dec 11;25(11):3047-3058.e4. doi: 10.1016/j.celrep.2018.11.043.
*Reserpine is used for the treatment of high blood pressure, usually in combination with a thiazide diuretic or vasodilator.
Last Editorial Review: January 2, 2019
Featured Image: Image of cancer woman having support of her family. Courtesy: ? 2010 ? 2019 Fotolia. Used with permission. Image 1.0:?Syrosingopine Courtesy:? ? 2010 ? 2019 Ciba/Novartis. Used with permission.
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