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Metabolic therapies inhibit tumor growth in vivo and in silico.

ABSTRACT: In the recent years, cancer research succeeded with sensitive detection methods, targeted drug delivery systems, and the identification of a large set of genes differently expressed. However, although most therapies are still based on antimitotic agents, which are causing wide secondary effects, there is an increasing interest for metabolic therapies that can minimize side effects. In the early 20th century, Otto Warburg revealed that cancer cells rely on the cytoplasmic fermentation of glucose to lactic acid for energy synthesis (called "Warburg effect"). Our investigations aim to reverse this effect in reprogramming cancer cells' metabolism. In this work, we present a metabolic therapy specifically targeting the activity of specific enzymes of central carbon metabolism, combining the METABLOC bi-therapeutic drugs combination (Alpha Lipoic Acid and Hydroxycitrate) to Metformin and Diclofenac, for treating tumors implanted in mice. Furthermore, a dynamic metabolic model describing central carbon metabolism as well as fluxes targeted by the drugs allowed to simulate tumors progression in both treated and non-treated mice, in addition to draw hypotheses on the effects of the drugs on tumor cells metabolism. Our model predicts metabolic therapies-induced reversed Warburg effect on tumor cells.

SUBMITTER: da Veiga Moreira J

PROVIDER: S-EPMC6395653 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Metabolic therapies inhibit tumor growth in vivo and in silico.

da Veiga Moreira Jorgelindo J Hamraz Minoo M Abolhassani Mohammad M Schwartz Laurent L Jolicœur Mario M Peres Sabine S

Scientific reports 20190228 1

In the recent years, cancer research succeeded with sensitive detection methods, targeted drug delivery systems, and the identification of a large set of genes differently expressed. However, although most therapies are still based on antimitotic agents, which are causing wide secondary effects, there is an increasing interest for metabolic therapies that can minimize side effects. In the early 20<sup>th</sup> century, Otto Warburg revealed that cancer cells rely on the cytoplasmic fermentation ...[more]

PMID: 30816152

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Project description:In the past ten years, many studies have shown that malignant tissue has been "normalized" in vitro using mechanical signals. We apply the principles of physical oncology (or mechanobiology) in vivo to show the effect of a "constraint field" on tumor growth. The human breast cancer cell line, MDA MB 231, admixed with ferric nanoparticles was grafted subcutaneously in Nude mice. The magnetizable particles rapidly surrounded the growing tumor. Two permanent magnets located on either side of the tumor created a gradient of magnetic field. Magnetic energy is transformed into mechanical energy by the particles acting as "bioactuators", applying a constraint field and, by consequence, biomechanical stress to the tumor. This biomechanical treatment was applied 2 hours/day during 21 days, from Day 18 to Day 39 following tumor implantation. The study lasted 74 days. Palpable tumor was measured two times a week. There was a significant in vivo difference between the median volume of treated tumors and untreated controls in the mice measured up to D 74 (D 59 + population): (529 [346; 966] mm3 vs 1334 [256; 2106] mm3; p = 0.015), treated mice having smaller tumors. The difference was not statistically significant in the group of mice measured at least to D 59 (D 59 population). On ex vivo examination, the surface of the tumor mass, measured on histologic sections, was less in the treated group, G1, than in the control groups: G2 (nanoparticles, no magnetic field), G3 (magnetic field, no nanoparticles), G4 (no nanoparticles, no magnetic field) in the D 59 population (Median left surface was significantly lower in G1 (5.6 [3.0; 42.4] mm2, p = 0.005) than in G2 (20.8 [4.9; 34.3]), G3 (16.5 [13.2; 23.2]) and G4 (14.8 [1.8; 55.5]); Median right surface was significantly lower in G1 (4.7 [1.9; 29.2] mm2, p = 0.015) than in G2 (25.0 [5.2; 55.0]), G3 (18.0 [14.6; 35.2]) and G4 (12.5 [1.5; 51.8]). There was no statistically significant difference in the day 59+ population. This is the first demonstration of the effect of stress on tumor growth in vivo suggesting that biomechanical intervention may have a high translational potential as a therapy in locally advanced tumors like pancreatic cancer or primary hepatic carcinoma for which no effective therapy is currently available.

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Metabolic therapies inhibit tumor growth in vivo and in silico.

Publications

Metabolic therapies inhibit tumor growth in vivo and in silico.

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