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US-12622886-B2 - Compositions comprising amino acids for prevention and/or treatment of cancer

US12622886B2US 12622886 B2US12622886 B2US 12622886B2US-12622886-B2

Abstract

Composition for use in the prevention and/or treatment of cancer in a subject, the composition comprising an active agent, said active agent containing the amino acids leucine, isoleucine, valine, threonine, lysine and citric acid, 5succinic acid, malic acid.

Inventors

  • Paolo Luca Maria Giorgetti

Assignees

  • PROFESSIONAL DIETETICS S.P.A.

Dates

Publication Date
20260512
Application Date
20201221
Priority Date
20200113

Claims (17)

  1. 1 . A method of treating cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of an active agent, said active agent comprising leucine, isoleucine, valine, threonine, lysine, and citric acid, succinic acid, and malic acid, wherein the active agent is free of arginine, serine, proline, and alanine, and wherein said cancer is selected from the group consisting of adenocarcinoma, melanoma, colorectal carcinoma and breast cancer.
  2. 2 . The method according to claim 1 , wherein the weight ratio between (i) the sum of citric acid, malic acid, and succinic acid and (ii) the sum of leucine, isoleucine, valine, lysine, and threonine is comprised between 0.05 and 0.3.
  3. 3 . The method according to claim 1 , wherein the weight ratio between (i) the overall amount of citric acid, malic acid, and succinic acid and (ii) the overall amount of leucine, isoleucine, and valine is comprised between 0.1 and 0.4.
  4. 4 . The method according to claim 1 , wherein the weight ratio between (i) citric acid and (ii) the sum of malic acid and succinic acid is comprised between 1.0 and 4.0.
  5. 5 . The method according to claim 1 , wherein the citric acid: malic acid: succinic acid weight ratio is comprised between 10:1:1 and 2:1.5:1.5.
  6. 6 . The method according to claim 1 , wherein said active agent further comprises at least one amino acid selected from the group consisting of histidine, phenylalanine, methionine, tryptophan, tyrosine, and cysteine.
  7. 7 . The method according to claim 1 , wherein said active agent further comprises histidine, phenylalanine, methionine, tryptophan, and cysteine.
  8. 8 . The method according to claim 1 , wherein the ratio between (i) the overall molar amount of citric acid, malic acid, and succinic acid and (ii) the overall molar amount of methionine, phenylalanine, histidine and tryptophan is higher than 1.35.
  9. 9 . The method according to claim 1 , wherein the ratio between (i) the overall molar amount of citric acid, succinic acid, and malic acid and (ii) the overall molar amount of lysine and threonine is comprised between 0.10 and 0.70.
  10. 10 . The method according to claim 1 , wherein the weight or molar amount of citric acid is higher than the overall weight or molar amount of both malic acid and succinic acid.
  11. 11 . The method according to claim 1 , wherein the weight ratio between leucine and citric acid is comprised between 5 and 1.
  12. 12 . The method according to claim 1 , wherein said active agent further comprises histidine, phenylalanine, methionine, tryptophan, cysteine and tyrosine.
  13. 13 . The method according to claim 5 , wherein the citric acid: malic acid: succinic acid weight ratio is comprised between 7:1:1 and 1.5:1:1.
  14. 14 . The method according to claim 5 , wherein the citric acid: malic acid: succinic acid weight ratio is comprised between 5:1:1 and 3:1:1.
  15. 15 . The method according to claim 7 , wherein the ratio between 1 the overall molar amount of citric acid, succinic acid, and malic acid and (ii) the overall molar amount of lysine and threonine is comprised between 0.15 and 0.55.
  16. 16 . The method according to claim 11 , wherein the weight ratio between leucine and citric acid is comprised between 2.50 and 3.50.
  17. 17 . A method of treating breast cancer in a subject comprising administering to the subject a) a therapeutically effective amount of an active agent, said active agent comprising leucine, isoleucine, valine, threonine, lysine, citric acid, succinic acid, and malic acid, and b) a therapeutically effective amount of doxorubicin, wherein the active agent and doxorubicin are administered simultaneously, separately or sequentially.

Description

This application is the U.S. national phase of International Application No. PCT/IB2020/062301 filed Dec. 21, 2020 which designated the U.S. and claims priority to IT 102020000000454 filed Jan. 13, 2020, the entire contents of each of which are hereby incorporated by reference. FIELD OF THE INVENTION The present description relates generally to compositions comprising amino acids for use in the prevention and treatment of cancer. BACKGROUND Cancers have a different metabolic profile with respect to normal tissues and contrasting evidence are emerging on the role of mitochondrial activity in the proliferation of cancer cells. The so-called Warburg effect, the preferential use of glucose even in presence of oxygen is one of the hallmarks of tumor cells. This phenomenon, initially defined as “aerobic glycolysis” led to the earliest hypothesis of a defective mitochondrial function in cancer. However, this setting has been shown to be more complex, and there is now general agreement that cancer mitochondria, during oncogenesis, engage in pleiotropic functions, such as macromolecular biosynthesis, apoptosis resistance, and activation of oncogenic signaling. Nevertheless, many mitochondrial mutations are indeed found in tumors, and a decreased oxidative phosphorylation (OXPHOS) rate has been shown, owing to a reduction in reactive oxygen species (ROS), to result in a proliferative advantage and an increase in cancer cell proliferation. Furthermore, given the pivotal role of glycolysis pathway in cancer growth, and since OXPHOS and glycolysis are reciprocally regulated, it is tempting to speculate that enhancing mitochondrial function could lead to glycolysis inhibition and cancer cell death. Moreover, much attention and efforts have been employed to develop glycolytic inhibitors as a pharmaceutic approach in anti-cancer therapy; some first and second generation drugs have been developed but their safety profile and development of resistance has raised some concerns. SUMMARY OF THE INVENTION The present description has the aim of providing new compositions particularly effective in the prevention and/or treatment of cancer and endowed with a safe administration profile. According to the present description, the above object is achieved thanks to the subject matter specifically recalled in the ensuing claims, which are understood as forming an integral part of this disclosure. An embodiment of the present description provides a composition for use in the prevention and/or in the treatment of cancer in a subject, the composition comprising an active agent, said active agent containing the amino acids leucine, isoleucine, valine, threonine, lysine and citric acid, succinic acid, malic acid. In one or more embodiments, the cancer may be selected in the group consisting of melanoma, adenocarcinoma, colorectal carcinoma, breast cancer. In one or more embodiments, the active agent of the composition may further contain one or more amino acids selected in the group consisting of histidine, phenylalanine, methionine, tryptophan, cysteine and tyrosine. BRIEF DESCRIPTION OF THE FIGURES The invention will now be described, by way of example only, with reference to the enclosed figures, wherein: FIG. 1 shows a MTT viability assay in cancer and normal cells incubated for the times indicated, with a normal media (DMEM) or with the composition of the instant application (α5). *p<0.01**p<0.05 vs DMEM. FIG. 2 shows a scratch wound assay in B16F10 melanoma cells at zero (0) hours and incubated for 24 hours (hr) in DMEM (NT) or with the α5 composition (α5). FIG. 3 shows a colony formation assay in HeLa cells incubated for 24 hr in DMEM (NT) or in the α5 composition (α5). FIG. 4 shows the results of western blot analysis of Cytochrome C (CytC) translocation and apoptosis markers in M14 melanoma cells incubated for 24 hr in DMEM (NT) or in the α5 composition (α5). TOP: α5 induces specific CytC, but not COX4, translocation in cytosol (PMS) of treated cells. BOTTOM: PARP-1 and caspase 3 cleavage in M14 cells. FIG. 5 shows the results of western blot analysis of mTOR pathway and HIF1α in cells incubated for 5 hr in DMEM (NT) or in the α5 composition (α5). LEFT: phospho-p70S6K (thr386) levels, as a marker of mTOR activity in M14, Hela, B16F10 and Detroit 573 fibroblasts. RIGHT: HIF1α expression in M14 and Hela cells. GAPDH is shown as a loading control. FIG. 6 shows the metabolic activity in cancer cell and in normal cells. Glycolysis (LEFT) and OCR (RIGHT) in HeLa, M14 and HL-1 cells after 1 hour of treatment with DMEM (NT) or in the α5 composition (α5). *p<0.01 vs NT. FIG. 7 is relative to MCF7 breast cancer cell proliferation. (A) Acid phosphatase assay: cells (5,000-20,000/well in 96-well plates) were treated with 1% α5 composition for 48 h and 1 μM doxorubicin (DOX) for 16 h. (B) Proliferation assay: cells (50,000/well in 12-well plates) were treated as in (A) and Trypan blue exclusion assay was used. n=3 experiments. *p<0.05 and **p<0