Glucose Adsorption Inhibitors to Inhibit Tumor Growth

Background:

I am writing this post in the context in which multiple readers and contributors to this website have shown interest in the potential of drugs and supplements that have the capability to inhibit glucose absorption in cancer cells. I am glad to see this interest as I also find this subject very relevant and would like to thank Ergin for triggering this subject. I actually discussed this part of this subject more than a year ago, showing the (to me) huge potential of glucose absorption inhibitors such as Phlorizin in cancer treatment as already demonstrated in humans.

As we often discussed , glucose is extremely important for tumors. It represents one of the main energy source and some tumors, when deprived of glucose can die. And if they do not die, at least they will further grow much slower and will be weaker and susceptible to other treatments such as chemo. All these aspects are basic knowledge, so well know that there is no need for reference to support these statements. For example, PET scan works exactly based on the fact that tumors like so much glucose.

If next to inhibiting glucose absorption we can also inhibit mitochondria function in cancer cells, there is an even higher chance that the tumors will be affected. But this subject, related to mitochondria modulation, will be discussed in details elsewhere. For now, here are a few examples of mitochondria inhibitors: Pyrvinium Pamoate, Meclizine, Doxycycline, Metformin (Ref.), Canagliflozin (Ref.) (thanks to Helga for pointing this out), Oligomicin (Ref.). The first five are FDA approved drugs currently used for various illnesses with a clear safety profile.

Glucose absorption:

Going back to glucose absorption, it is known that glucose is transported into the cells via two classes of hexose transporters, namely,

• the SGLT (sodium-dependent glucose transporter) family and
• the GLUT (facilitative glucose transporter) family,

and that SGLTs transport glucose against the concentration gradient whereas GLUTs do so along the gradient (Ref.).

SGLT2 has a greater transport capacity and reabsorbs glucose in combination with sodium in the ratio 1:1. SGLT1 has a higher affinity for glucose and reabsorbs glucose in combination with sodium in the ratio 1:2. Note that both transporters are secondarily active owing to their dependence on the activity of the Na⁺/K⁺-ATPase for the active removal of sodium (Ref.) Also note that this is a connection point between sodium-based glucose absorption and the cardiac glycosides (such as oleander, bufalin, etc.) which are Na⁺/K⁺-ATPase inhibitors and as a result will also lower the function of SGLT1 and SGLT2.

The glucose transporters are very relevant for all the cells, since they represent the doors for the glucose to enter the cells.

Nearly all cancer types have some of these transporters over expressed in order to deal with the short-term high-energy required to develop fast. Because, cancer cells are using most of the glucose in an inefficient way, from the energy production point of view (that is called fermentation or glycolisis), they require large amounts of glucose and thus a large number of glucose transporters on their membrane.

However, it is very important to realize that in normal conditions most cancer cells are over-expressing GLUT transporters (specifically GLUT1) and very little SGLT transporter types. There is a large amount of literature supporting this (Ref.1, Ref.2, Ref.3, Ref.4, etc.). In addition, GLUT1 has been also shown to be highly relevant against Cancer Stem Cells (Ref.)

To have a feeling on the over expression of GLUT1 in various cancer cell types here is the protein atlas database showing that: http://www.proteinatlas.org/ENSG00000117394-SLC2A1/cancer

And here is the expression of SGLTs in various cancer cell types:

• SGLT1 http://www.proteinatlas.org/ENSG00000100170-SLC5A1/cancer
• SGLT2 http://www.proteinatlas.org/ENSG00000140675-SLC5A2/cancer

Indeed, it has been shown that not all the SGLT2 inhibitors can reduce the glucose absorption in cancer cells. For example Canagliflozin, but not Dapagliflozin could decrease glucose uptake in prostate and lung cancer cells and it has been suggested to be a result of the fact that Canaglifozin is also an inhibitor of SGLT1 and possibly GLUT1 (Ref.). In addition, Canagliflozin seems to also have an off target action against cancer cells via the activation of AMP-activated protein kinase (AMPK) and as a result decrease mitochondrial respiration.

But things are not that simple …

In contrast to the above suggesting that SGLTs are not that relevant in cancer, there is a relatively recent study making things a bit more complex, as it shows that in some cases SGLT2 inhibitors can actually kill cancer cells such as those of pancreas and prostate via glucose absorption inhibition (Ref.). This is strange since most of the literature indicates that SGLT2 is not that relevant in cancer.

In order to make sense out of that, and unify both “sides” of the research, here is how we could understand it:

• Glucose absorption via SGLTs requires the right sodium gradient that is “arranged” by the Na/K transporter but that costs energy (ATP).
• In contrast to that, glucose import via GLUTs does not require energy as it simply depends on the glucose gradient.
• Typically, when there is enough glucose in the blood, cancer cells will express GLUT1 only, since glucose will flow in the cancer cells without the need for the cell to spend energy
• However, when there is not enough glucose in the blood the cancer cell has to “start the engine”, over express SGLTs that require energy in order to extract the little glucose that is available around the tumor cells
• This is how the scientists also understand the mechanism (Ref.)
• If the above is true, you could expect that there will be more SGLT over-expression at the center of the tumor (hypoxic area) where there may be less glucose available. Indeed, the hypoxic area is also the one that will be most dependent on glucose since it can not use mitochondria to produce energy due to the lack of oxygen
• And yes, if I look at the picture of the tumor, Canagliflozin (next to gemcitabine) used in this study lead to an increase necrotic area at the center of the tumor which is typically more resistant to treatments.
• Even more, Dapagliflozin (next to gemcitabine) cause the necrosis in the tumors that were larger, i.e. the higher the tumor, the more necrotic area (Ref.) which I would expect since it does not have impact on GLUT1 as Canagliflozin does, but is very specific to SGLT2 which will only start to be over-expressed when there is no glucose which should be the case even more at the center of large tumors.
• Based on the above you could argue that we should chose between e.g. Dapagliflozin and Canagliflozin depending on the tumor size and glucose status in the body.
• Therefore, Dapagliflozin may be more relevant for the very large tumors, while Canagliflozin may be more relevant for smaller tumors in people with high blood glucose levels (e.g. who do not follow a low-sugar diet and do not use other glucose lowering medication).

Glucose absorption inhibitors:

Therefore, inline with the literature, inhibition of glucose transport is a great tool to fight against cancer and also support other treatments such as chemo, radiation, new treatments such as 3BP, Salinomycin, etc. Best is to also combine it with a mitochondrial modulator such as those discussed above, e.g. Metformin.

From an effectiveness point of view, best would probably be to combine GLUT1 + SGLT2 inhibitors. But such combination may be too effective and that could be dangerous to normal cells as well.

This is why, I would focus first on GLUT1 inhibitors since GLUT1 is expressed in normal conditions and since GLUT1 inhibition by Phlorizin has already been shown to be effective in humans (Ref.). Here is a list of such inhibitors:

• Phlorizin/Phloretin– probably some of the most effective GLUT1 inhibitors I know and already shown to lead to amazing results in humans (Phlorizin is also a SGLT inhibitor). The draw back is that it can only be used IV since the oral absorption is too low.
• Canagliflozin – according to the reference cited above, it also inhibits GLUT1. Fortunately, this drug is available as a tabled under the name Invokana. It has been recently approved for the use in diabetics. Wholesale price of Invokana is $8.77 per tablet, or $263.10 for a one-month supply. Retail pharmacy prices are about $349 to $405. (Ref.) This is a drug from the chategory of gliflozins
• Verapamil – this is a “heart-drug” available anywhere across the world and cheap, also known for its capabilities to reduce the multi drug resistance of cancer cells and increase chemo effectiveness (Ref.). It has been found to also act as a GLUT1 inhibitor (Ref.)

Other GLUT1 inhibitors, but probably less effective compared to the above are Diclofenac via the inhibition of MYC (Ref.), Fisetin, myricetin, quercetin, apigenin, genistein, cyanidin, daidzein, hesperetin, naringenin, catechin, Graviola.

If the patient is on e.g. ketogenic diet or if we can not access one of the GLUT1 inhibitors, we may want to consider a SGLT inhibitor such as:

• drugs from the category of Gliflozins including: Canagliflozin, Dapagliflozin, Empagliflozin, ‎Ipragliflozin, Tofogliflozin. Other drugs in development under the same category are Remogliflozin etabonate, Ertugliflozin, Sotagliflozin.

SGLT2 inhibitors should fit nicely ketogenic diet since SGLTs are probably over-expressed in those patients.

Note: canagliflozin and derivatives has been patented as a treatment of cancer https://www.google.com/patents/WO2016134486A1?cl=en

Conclusion:

When having to deal with cancer, I would strongly consider the IV treatment with Phlorizin or the oral drugs such as Canagliflozin and Dapagliflozin. They could be used:

• together with chemotherapy or radiotherapy to increase treatment effectiveness
• together with new treatments such as 3BP, Salinomycin to increase treatment effectiveness
• together with mitochondria inhibitors such as Metformin

References:

Functional expression of sodium-glucose transporters in cancer https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4522748/

Cancers require high amounts of glucose to grow and survive, and dogma is that uptake is facilitated by passive glucose transporters (GLUTs). We have identified a new mechanism to import glucose into pancreatic and prostate cancer cells, namely active glucose transport mediated by sodium-dependent glucose transporters (SGLTs). This means that the specific radioactive imaging probe for SGLTs, α-methyl-4-deoxy-4-[18F]fluoro-d-glucopyranoside, may be used along with positron-emission tomography to diagnose and stage pancreatic and prostate cancers, tumors in which the GLUT probe 2-[18F]fluoro-2-deoxy-d-glucose has questionable utility. Moreover, we suggest, based on our results in mouse models, that Food and Drug Administration-approved SGLT2 inhibitors may be used to reduce the viability of pancreatic and prostate cancer cells in patients.

Verapamil inhibits the glucose transport activity of GLUT1 https://www.ncbi.nlm.nih.gov/pubmed/20354917

Calcium channel blocker toxicity has been associated with marked hyperglycemia responsive only to high-dose insulin therapy. The exact mechanism(s) of this induced hyperglycemia has not been clearly delineated. The glucose transporter GLUT1 is expressed in a wide variety of cell types and is largely responsible for a basal level of glucose transport. GLUT1 also is activated by cell stress. The specific purpose of this study was to investigate the effects of the calcium channel blocker verapamil on the glucose uptake activity of GLUT1 in L929 fibroblasts cells. Dose-dependent effects of verapamil on glucose uptake were studied using L929 fibroblast cells with 2-deoxyglucose. Verapamil had a dose-dependent inhibitory effect on both basal and stress-activated transport activity of GLUT1. Basal activity was inhibited 50% by 300 μM verapamil, while 150 μM verapamil completely inhibited the activation induced by the stress of glucose deprivation. These effects were reversible and required verapamil to be present during the stress. Alteration of calcium concentrations by addition of 5 mM CaCl₂ or 4 mM EDTA had no effect on verapamil action. This study reveals the unique finding that verapamil has inhibitory effects on the transport activity of GLUT1 independent of its effects on calcium concentrations. The inhibition of GLUT1 may be one of the contributing factors to the hyperglycemia observed in CCB poisoning.

The diabetes medication Canagliflozin reduces cancer cell proliferation by inhibiting mitochondrial complex-I supported respiration. https://www.ncbi.nlm.nih.gov/pubmed/27689018

These data indicate that like the biguanide metformin, Canagliflozin not only lowers blood glucose but also inhibits complex-I supported respiration and cellular proliferation in prostate and lung cancer cells. These observations support the initiation of studies evaluating the clinical efficacy of Canagliflozin on limiting tumorigenesis in pre-clinical animal models as well epidemiological studies on cancer incidence relative to other glucose lowering therapies in clinical populations.

GLUT1 as a therapeutic target in hepatocellular carcinoma. https://www.ncbi.nlm.nih.gov/pubmed/19874261

Primary hepatocellular carcinoma (HCC) is one of the most fatal cancers in humans with rising incidence in many regions around the world. Currently, no satisfactory curative pharmacological treatment is available, and the outcome is mostly poor. Recently, we have shown that the glucose transporter GLUT1 is increased in a subset of patients with HCC and functionally affects tumorigenicity. GLUT1 is a rate-limiting transporter for glucose uptake, and its expression correlates with anaerobic glycolysis. This phenomenon is also known as the Warburg effect and recently became of great interest, since it affects not only glucose uptake and utilization but also has an influence on tumorigenic features like metastasis, chemoresistance and escape from immune surveillance. Consistent with this, RNA-interference-mediated inhibition of GLUT1 expression in HCC cells resulted in reduced tumorigenicity. Together, these findings indicate that GLUT1 is a novel and attractive therapeutic target for HCC. This review summarizes our current knowledge on the expression and function of GLUT1 in HCC, available drugs/strategies to inhibit GLUT1 expression or function, and potential side effects of such therapeutic strategies.

GLUT, SGLT, and SWEET: Structural and mechanistic investigations of the glucose transporters https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4815417/

Glucose is the primary fuel to life on earth. Cellular uptake of glucose is a fundamental process for metabolism, growth, and homeostasis. Three families of secondary glucose transporters have been identified in human, including the major facilitator superfamily glucose facilitators GLUTs, the sodium‐driven glucose symporters SGLTs, and the recently identified SWEETs. Structures of representative members or their prokaryotic homologs of all three families were obtained. This review focuses on the recent advances in the structural elucidation of the glucose transporters and the mechanistic insights derived from these structures, including the molecular basis for substrate recognition, alternating access, and stoichiometric coupling of co‐transport.

Attacking the supply wagons to starve cancer cells to death https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4833639/

The constitutive anabolism of cancer cells supports proliferation but also addicts tumor cells to a steady influx of exogenous nutrients. Limiting access to metabolic substrates could be an effective and selective means to block cancer growth. In this review, we define the pathways by which cancer cells acquire the raw materials for anabolism, highlight the actionable proteins in each pathway, and discuss the status of therapeutic interventions that disrupt nutrient acquisition. Critical open questions to be answered before apical metabolic inhibitors can be successfully and safely deployed in the clinic are also outlined. In summary, recent studies provide strong support that substrate limitation is a powerful therapeutic strategy to effectively, and safely, starve cancer cells to death.

Use of canagliflozin and derivatives thereof in the treatment of cancer https://www.google.com/patents/WO2016134486A1?cl=en

The use of canangliflozin and derivatives thereof in the treatment and prevention of cancer is disclosed. Said compounds have been previously determined to be selective sodium glucose transporter 2 (SGLT2) inhibitors useful in the treatment of diabetes with effects that are similar to metformin. Canagliflozin has now been determined to activate AMP-activated protein kinase (AMPK) and inhibit the growth of a range of cancers. Further to this, use of canagliflozin in combination with other chemotherapeutics has now been determined to give rise to increased anti-cancer activity.

Preventive effects of the sodium glucose cotransporter 2 inhibitor tofogliflozin on diethylnitrosamine-induced liver tumorigenesis in obese and diabetic mice.

Sodium glucose cotransporter 2 inhibitors are expected to ameliorate the abnormalities associated with metabolic syndrome including non-alcoholic fatty liver disease. In this study, we investigated the effects of the sodium glucose cotransporter 2 inhibitor tofogliflozin on the development of non-alcoholic fatty liver disease-related liver tumorigenesis in C57BL/KsJ-+Leprdb/+Leprdb obese and diabetic mice. The direct effects of tofogliflozin on human liver cancer cell proliferation were also evaluated. Mice were administered diethylnitrosamine-containing water for 2 weeks and were treated with tofogliflozin throughout the experiment. In mice treated with tofogliflozin, the development of hepatic preneoplastic lesions was markedly suppressed, and hepatic steatosis and inflammation significantly reduced, as evaluated using the non-alcoholic fatty liver disease activity score, in comparison with the control mice. Serum levels of glucose and free fatty acid and mRNA expression levels of pro-inflammatory markers in the liver were reduced by tofogliflozin treatment. Conversely, the proliferation of sodium glucose cotransporter 2 protein-expressing liver cancer cells was not inhibited by this agent. These findings suggest that tofogliflozin suppressed the early phase of obesity- and non-alcoholic fatty liver disease-related hepatocarcinogenesis by attenuating chronic inflammation and hepatic steatosis. Therefore, sodium glucose cotransporter 2 inhibitors may have a chemopreventive effect on obesity-related hepatocellular carcinoma.