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Two years ago, the University of Basel’s Don Benjanmin research team published an article in the journal Science Advance, saying that the antihypertensive drug syrosingopine (silosepine) significantly enhanced the anti-tumor efficacy of metformin, causing the medical community. Extensive discussion: Metformin plus carbazone is an anticancer drug?

But the research two years ago is only a new discovery, and the specific mechanism of action is still unclear.

On December 11th, the research team further unveiled the mystery of this “drug cocktail”: further breaking its energy supply and killing cancer cells by breaking the regeneration cycle mechanism of NAD+ in cancer cells.

In addition, there is another major finding in this study. It was thought that the antihypertensive antihypertensive drug cilostazine, which is an anti-cancer anticancer drug, turned out to be a dual MCT1/4 inhibitor of cancer, which could trigger the synthetic lethality of metformin.
Block NAD+ regeneration cycle, trigger cancer cell energy crisis

An important hallmark of cancer is the increase in energy metabolism from oxidative phosphorylation to glycolysis. Compared to oxidative phosphorylation, the glucose required for glycolysis increases significantly, and NAD+ is the key to the conversion of nutrients into energy. Under normal circumstances, NAD+ in cancer cells can be regenerated.

The researchers found that the main mechanism of action of “drug cocktails” in combination with anti-cancer is to block the NAD+ regeneration pathway, resulting in the depletion of NAD+, which triggers the energy crisis of cancer cells.

According to Don Benjamin, the lead author of the study, “Metformin and cilostazol can prevent the regeneration of NAD +, but in two different ways.”

Reductive coenzyme I (NADH) and lactate dehydrogenase (LDH) are important substances for maintaining the regeneration cycle of NAD + required for glycolysis. NADH is the reduced state of NAD+. LDH is a glycolytic enzyme. LDH exists in the cytoplasm of all tissue cells of the body and can catalyze the conversion of pyruvate to lactic acid, accompanied by the oxidation process of NADH to NAD+.

Metformin directly inhibits NADH from oxidation to NAD+. However, the anticancer activity exhibited by metformin using a conventional antidiabetic dose (μM range) is minimal, and studies have previously confirmed that the concentration of metformin exhibiting anticancer activity in the preclinical model is in the range of mM, which is more than conventional resistance. The concentration of metformin in the dose of diabetes is up to an order of magnitude higher, which will undoubtedly cause great toxicity to the body.

Another major pathway to block NAD + regeneration is to indirectly reduce NAD+ levels by inhibiting the catalytic response of LDH.

So how to inhibit the catalytic reaction of LDH?

The authors say, “Inhibition of lactic acid end products can solve this problem perfectly.” Because glycolysis produces ATP less efficiently, cancer cells need to increase glucose uptake to compensate for glycolysis rates. This can result in an excess of lactic acid production, resulting in intracellular acidification. In turn, cytosolic acidification also reduces the rate of glycolysis by inhibiting the rate-limiting enzyme PFK1. Therefore, cancer cells need to constantly exclude lactic acid and H + to prevent intracellular acidification.

Ciprofloxacin indirectly blocks the regeneration cycle of NAD+ by inhibiting the lactate transporter MCT in cancer cells.
Ciclofloxacin has dual inhibitory effects on MCT1/4 target

In fact, scientists have previously shown that the accumulation of lactic acid in malignant tumors can promote tumor growth and metastasis, and MCT is a very valuable cancer target.

Four lactate transporters MCT1, MCT2, MCT3, and MCT4 are known. MCT1 is ubiquitously expressed and has high affinity for lactic acid (3-6 mM). It is the major lactate transporter under normal conditions of low intracellular lactate levels. MCT2 is expressed in the brain, liver and renal tubules. MCT3 is expressed in the choroid plexus and retina. MCT4 is expressed by hypoxia-inducible factor 1α (HIF-1α) in a hypoxic environment. MCT4 is a marker of poor prognosis in a variety of cancers.

Since the scientific community is very inadequate on MCT2 and MCT3, MCT1/4 has also become the last hope. Previously, studies have shown that pharmacological or hereditary elimination of MCT1 or MCT4 activity can result in reduced proliferation of cancer cells in vitro and in vivo.

However, although scientists have made considerable efforts to develop pan-MCT1 or MCT4-specific inhibitors, they have not been successful. The only effective small-molecule MCT inhibitor developed to date is MCT1, which is currently in Phase I clinical trials. Moreover, AZD3965 is ineffective for MCT4 expression. It is therefore also restricted to be applied to tumors overexpressing MCT4. The antihypertensive drug cilostazate has double inhibition on MCT1/4, which is conceivable and its importance. In this test, it was demonstrated that the inhibitory effect of ciprofloxacin on MCT4 was more significant, which was 60 times higher than that of MACT1.

Many authoritative science websites said, “This antihypertensive drug syrosingopin, which was developed and marketed in 1958, can be used as a MCT1/4 dual inhibitor, which may have opened its second career – anti-cancer!”

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