Potential Use of Gluconate in Cancer Therapy

Abstract

We have recently discovered that cancer cells take up extracellular citrate through plasma membrane citrate transporter (pmCiC) and advantageously use citrate for their metabolism. Citrate uptake can be blocked with gluconate and this results in decreased tumor growth and altered metabolic characteristics of tumor tissue. Interestingly, gluconate, considered to be physiologically neutral, is incidentally used in medicine as a cation carrier, but not as a therapeutically active substance. In this review we discuss the results of our recent research with available literature and suggest that gluconate may be useful in the treatment of cancer.

Extracellular Citrate Fuels Cancer Cell Metabolism and Growth

“…Moreover, blocking of mCiC with BTA should decrease ROS synthesis due to the decreased mitochondrial activity rather than increase it (Fernandez et al, 2018). Most of these discrepancies could be potentially explained by our recent data showing that cancer cells of different origin can take up extracellular citrate through the plasma membrane citrate transporter pmCiC (Mycielska and Geissler, 2018;Mycielska et al, , 2019, which is a variant of the mitochondrial SLC25A1 (mCiC). pmCiC has a different start codon which is located in the intron preceding second exon of the mCiC (Mazurek et al, 2010).…”

<p>Gluconokinase IDNK Promotes Cell Proliferation and Inhibits Apoptosis in Hepatocellular Carcinoma</p>

“…Gluconate has been reported to be able to block citrate transport to cancer cells and inhibit tumor growth, which has been raised as a candidate option for diagnosis and treatment of cancers. 13 Considering that IDNK plays a vital role in gluconate metabolism, we speculated that inhibition of IDNK expression may block gluconate metabolism, thereby preventing cancer cell growth.…”

“…Another study described the behavior of gluconate as the competitive and irreversible blocker of citrate transport, with the inhibition of cancer cell growth in immunodeficient mice. 13 Thus, increasing the level of gluconate could inhibit the oxidation of citrate oxidizing, therefore inhibiting cancer cell proliferation and promoting apoptosis. The intriguing discovery of IDNK in the control of HCC cancer cell proliferation may inspire future studies about the mechanism.…”

“…9 Recent evidence indicated an inhibitory effect of gluconate on tumor growth by competitive blocking of pmCiC. 10 Gluconokinase has a key role in gluconate metabolism in humans. 11 The IDNK gene encodes human gluconokinase, which is involved in the phosphorylation of gluconate.…”

The Mitochondrial Citrate Carrier SLC25A1/CIC and the Fundamental Role of Citrate in Cancer, Inflammation and Beyond

“…Moreover, SLC13A5 is induced in DIO livers treated with CTPI-2, coinciding with a reduction in the concentration of serum citrate, thus suggesting that this protein can provide a mechanism of compensation when CIC is inhibited [ 16 ]. With this in mind, combinatorial therapy with CTPI-2 and SLC13A5 inhibitors (e.g., gluconate [ 29 ]) is likely to be more effective than treatment with either agent alone in NAFLD/NASH.…”