Starting point of KAT
There are several generations of therapies which coexist as anticancer agents.
But still the conquest of cancer is far away.
The biggest problem of anticancer treatment currently present is toxicity.
In other words, because there is no selectivity for cancer cells.
We are developing an anti-cancer agent that is referred to as the fourth generation of anticancer agents.
KAT refers to the anti-cancer treatment technology developed by Dr. Ko KAT = Kodiscovery Anticancer Technology
This technique stems from a small molecule called 3-bromopyruvate (3BP) discovered by Dr. Young Hee Ko when Dr. Ko was working in Pedersen's lab. Dr. Ko and Pedersen studied together since 1991.
As specially designed by Dr. Ko, while tumor cells are rapidly destroyed when treated with 3BP, normal cells are not affected.
This is because the monocarboxylic acid transporters (MCTs) levels do not rise in normal cells, unlike tumor cells.
As Dr. Ko and Pedersen Explained, MCT is a transport channel where 3BP can enter the inside of tumor cells. Once inside, 3BP quickly destroys all of the tumor cell's power plant (glycolysis and OxPhos).
Tumor cells die quickly through cell death (apoptosis) or necrosis and energy decreases rapidly.
3BP: Structure & Chemical Reaction
The reason 3BP has this selectivity is due to the similarity with the structures of pyruvic acid & lactic acid as shown below.
3BP transforms proteins with (-SH, -NH2), nucleic acid bases and metabolites. As a result of chemical reaction in such a cancer cell, the metabolism of the cancer cell is disrupted.
Two mechanisms of 3BP
The 3BP in the cancer cells has two major mechanisms
First, block of energy metabolism in cancer cells.
Second, The recovery of the apoptosis function of cancer cells.
First, let's look at a mechanism that interferes with the energy metabolism of cancer cells.
Mechanism 1: Cutting the Fuel Line of the Cancer Cells
- Compared to normal cells, cancer cells produce elevated amounts of lactic acid in the presence of O2 (Warburg Effect)
- Lactic acid transporters (monocarboxylate transporters) are up-regulated in cancer cells
- Due to structural similarity to lactic acid, 3BP enters cancer cells preferentially
- Inside cancer cells, 3BP inhibits the two power plants (glycolysis & mitochondrial oxidative phosphorylation)
- The cellular energy (ATP) reserves are rapidly depleted
Trojan Horse Hypothesis for Selective Action of 3BP on Cancer Cells
(Sneaks in through Doors that Lactate Goes out and Destroys “Power Plants”.)
Mechanism 2: VDAC＇s functional recovery (apoptosis)
Mitochondrial-bound hexokinase (HK) II plays a major role in preventing tumor apoptosis.
Right: Without control mechanisms in place to prevent it, cell death would be highly likely within the unfavorable conditions that exist in a tumor microenvironment. Thus, caspase-mediated induction of apoptosis would be facilitated first by activation of the mitochondrial permeability transition pore complex (MPTP), indicated on the right by a question mark (?), that in turn would facilitate the release to the cytoplasm of the caspase activator cytochrome c (located within the inter-membrane space). Bcl-2-related proteins (Bax and Bad) would likely overcome effects of the MPTP inhibiting protein Bcl-XL and help facilitate release of cytochrome c.
Left: By populating mitochondrial voltage-dependent anion channels (VDACs) with HK II and by persistent channeling of adenine nucleotides, opening of the MPTP is inhibited. This in turn inhibits access of VDACs to Bax and Bad, and most likely maintains cytochrome c in a state favorable for its mitochondrial retention in the inter-membrane space. Thus, HK II helps assure a highly malignant tumor’s proliferation, and its escape from cell death, under conditions that would otherwise favor this process.
Metabolic Targeting Therapeutic Strategies
Drugs that interfere with energy metabolism, such as 3BP are currently being studied in a few ways.
In the figure below, we summarized the drugs that work in the course of 1 to 6.
(1) Targeting key enzymes(hexokinase 2) in the Early Stage glycolysis > 3BP, DG(Deoxyglucose), Lonidamine
(2) Inhibit ATP synthasome (ATP synthase / adenine nucleotide carrier / phosphate carrier complex) > 3BP
(3) Target lactate efflux > alpha cyano 4-hydroxy cinnamic acid (ACCA)
(4)(5) Target lactate dehydrogenase(LDH), pyruvate dehydrogenase(PDH), pyruvate dehydrogenase kinase(PDHK)
which related to mitochondrial pyruvate entry > 3BP (Inhibit LDH), DCA (Inhibit di-chloroacetate ;PDHK)
(6) Target Pyruvate kinase > MITAPIVAT (Agios) activates pyruvate kinase-R (PKR) that appears in red blood cells to treat PK deficiency
(Phase 2/3, Orphan drug & Fast Track designation)
Etc. : Reduce tumor transfer by neutralizing low pH in tumor microenvironment > bicarbonate therapy, 3BP therapy
3BP drops the ATP level below 20% by blocking the generation of ATP in the energy metabolism of cancer simultaneously in various processes.
In other words, it is to kill the cancer cells.