EP4351572A1 - Polythérapie à base d'un agent de saponine et d'un agent anthelmintique contre le cancer - Google Patents

Polythérapie à base d'un agent de saponine et d'un agent anthelmintique contre le cancer

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Publication number
EP4351572A1
EP4351572A1 EP22733921.5A EP22733921A EP4351572A1 EP 4351572 A1 EP4351572 A1 EP 4351572A1 EP 22733921 A EP22733921 A EP 22733921A EP 4351572 A1 EP4351572 A1 EP 4351572A1
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EP
European Patent Office
Prior art keywords
cancer
agent
body weight
composition according
effective amount
Prior art date
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Pending
Application number
EP22733921.5A
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German (de)
English (en)
Inventor
Yousef M A KH M ALENEZE
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Raincastle Bio Ltd
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Raincastle Bio Ltd
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Publication date
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Publication of EP4351572A1 publication Critical patent/EP4351572A1/fr
Pending legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7032—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a polyol, i.e. compounds having two or more free or esterified hydroxy groups, including the hydroxy group involved in the glycosidic linkage, e.g. monoglucosyldiacylglycerides, lactobionic acid, gangliosides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/5123—Organic compounds, e.g. fats, sugars
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to the field of treating cancer.
  • the pre sent disclosure relates to a combination treatment for cancer as well as composi tions to be used in the treatment of cancer.
  • Multi-clonal tumors are major setbacks to moleclarly-targeted therapies (which only inhibit subsets of certain tumor clones that host the druggable oncogenic targets), thus rendering other competing tumor subclones (with undruggable oncogenic tar gets) resistant to such treatments.
  • tumor stem cells exhibit stem like properties with limited proliferation particularly upon exposure to treatment yet retain self-renewal capacity (cancer stem cells or CSCs) which could result in tumor relapse.
  • CSCs could also migrate to distant organs and form distant metastatic tumors with more diverse tumor sub clones, particularly under increased selective pressures of survival, thus certain emerging subclones will develop increased resistance to chemotherapy and mo- lecular targeted therapy which will further progress to aggressive tumor retard sion, worse prognosis and poor survival.
  • chemotherapy leads to poor quality of life due to well- documented side effects, including cancer cachexia (muscle wasting and loss of appetite), associated with high pro-inflammatory TNF-alpha levels, chemotherapy induced alopecia due to non-specific targeting of high proliferative cells, fatigue and physical (including bone cancer pain) and neurological pain through IL-6-TRPA1 and TNF-alpha-TRPA1 pathways (Liu et al., 2019).
  • IL-6-TRPA1 and TNF-alpha-TRPA1 pathways Liu et al., 2019.
  • Blocking IL-6 and TNF-alpha was shown to be beneficial in inhibiting pain in in-vivo models including chemotherapy-induced pain.
  • autoimmune-like im mune related adverse events commonly arises in patients.
  • Persistence in T-cell responses, through in-hibiting T-cell exhaustion (via ICIs) could prolong the expression of inflammatory cytokines and could trigger self-antigen presentation alongside tumor antigen presentation; thus, targeting both tumor and surrounding inflamed target organ or tissue (Konig & Laubli, 2020).
  • Post-mortem studies show ed that melanoma cancer patients receiving ICIs led to immune infiltration in the myocardial tissue which developed into myocarditis (GOrdogan, 2020).
  • IL-6 is also known to be a surrogate of immune response, inflammation, tumor progression and pain. Serum IL-6 is associated with worse prognosis and poor sur vival in cancer patients.
  • iRAEs such severe arthri-tis, myocarditis, uveitis, gre at vasculitis, severe pneumonia, great vasculitis, and myasthenia gravis
  • Tocili- Kursab Anti IL-6 Receptor antibody
  • Targeting IL-6 pathway does not activate tumor progression.
  • tumor cell killing without over-expression of IL-6 and/or activate IL-6 sig nalling pathways and other inflammatory cytokines pose as great benefit for pati ents such as inhibit-ing cancer cachexia, physical and neuropathic pain and fatigue- thus contributing towards improving quality of life.
  • This invention presents the combination of Ginsenoside and Mebendazole to trigger im-mune-mediated tumor cell killing without the secretion of IL-6. Therefore, Ginse noside and Mebendazole combination reduces cytokine release commonly associa ted with cancer cachexia, physical and neuropathic pain, fa-tigue and poor quality of life.
  • Ginsenoside a bioactive saponin compound found in Panax ginseng in trace amounts, poses anti-proliferative and pro-apoptotic effects in tumors. Ginsenoside contributes to both extrinsic apoptosis (via Death receptors such as FAS and TRAIL) and intrinsic mitochondrial apoptosis, resulting in caspase 8 and caspase 3/7 activation downstream.
  • activated caspase 8 could also indirectly activate caspase 3/7 by trun cating BID, a pro-apoptotic protein, into its functional form tBID; tBID then contribu tes to translocating BAX to the mitochondria to re-lease mitochondrial cytochrome c thus triggering intrinsic apoptosis as well.
  • Tumors generally live in harsh pathophysiolog ical conditions such as low glucose and hypoxia which trigger intracellular ER stress and impairment in protein folding, lipid metabolism and calcium level regula tion.
  • Ginsenoside increases ER stress towards which expressing death receptors such as DR4 and DR5 receptors in tumors via PERK-ATF4-CHOP pathway; this primes cancer cells for extrinsic apoptosis upon interaction with cells that strongly express TRAIL (ligand) particularly, activated T cells and monocytes (Lam et al. , 2020; Martin-Perez et al., 2011).
  • TRAIL ligand
  • Akt also phosphorylates BAX at Serine 184 residue (S184) which causes BAX to inhibit apoptosis.
  • Ginsenosides inhibit Akt-pathway and disrupt plasma membrane lipid rafts (sphingolipid and cholesterol enriched micro domains of transmembrane proteins found clustered together which serve as external components of cell sig nalling pathways). This inactivates the pro-surivival Akt pathway and helps to ra pidly and strongly translocate BAX into the mitochondria, thus further triggering mi tochondrial-based intrinsic apoptosis.
  • Mebendazole an anti-helminth drug, ad-dresses the three strategies above by (i) phosphorylating and deactivating BCL-2 protein, (ii) enhance T-cell activation through increased clustering and interaction between CD14+monocytes/macrophages and T-cells and (iii) re-polarize immuno suppressive tumor-promoting M2 macrophages to M1 classically activated anti tumor macrophages which can directly kill the tumor and provide chemokine sig nals to increase immune infiltration of activated immune cells expressing TRAIL could interact with TRAIL-sensitized tumor cells to induce cancer cell death.
  • the tumor cell death is based on extrinsic death receptor-based and intrinsic mitochondrial-based apoptotic pathways, sug-gestively through direct interaction of death ligands in activated immune cells and death receptors in tumor cells; where ginsenosides up-regulate death receptors in stressed malnourished or hypoxic cells (such as tumor cells), while mebendazole enhances T-cell activation and limits intracellular anti-apoptotic proteins in cancer cells.
  • This provides a strategy to selectively target different malignant cells of different tissue origins while keeping physiologically unstressed cells in-tact and non- targeted, particularly hair follicles of cancer patients.
  • MDA-MB-231 Breast cancer cell line (BRAF mutant, CDKN2A mutant, K-RAS mu tant, TP53 mutant)
  • HCT-116 Colon cancer cell line K-RAS mutant, PIK3CA mutant
  • PANC-1 Pancreatic cancer cell line K-RAS mutant, TP53 mutant, CDKN2A mu tant
  • HepG2 Liver cancer cell line (CTNNB1 mutant, TERT mutant, NRAS mutant)
  • liver diseases can be categorised into: (i) viral hepatitis, (ii) genetic, (iii) drug or toxins-related, (iv) autoimmune disorders, (v) fatty liver disease and (vi) cancer. Although originated by different aetiologies all will lead, if untreated, to the formation of chronic liver fibrosis/cirrhosis which will ultimately affect the microana- tomy and function of the liver.
  • fibrosis and its latest stage, cirrhosis affects and alters the quantity and quality of ECM, specifically collagen, leading to the for mation of scar tissue (Williams).
  • Myofibroblasts are the source of ECM overproduc tion during the development of fibrosis (Lim). Myofibroblasts are not found in a nor mal, healthy liver and their origin is hepatic stellate cells (Kisseleva). Additionally, inflammation and autophagy occur during hepatic fibrosis development. Chronic inflammation in liver is an immune response that persists for months leading to tis sue remodelling, and repair processes. Regardless of aetiology, chronic liver in flammation induces hepatic fibrosis that eventually leads to cirrhosis and hepatocel lular carcinoma which is a leading cause of death worldwide (Dhar et al.).
  • the pivotal event in preventing the progression of hepatic fibrosis is to reduce the activation and transition of hepatic stellate cells into myofibroblasts or to promote hepatic stellate cells’ senescence and apoptosis (Higashi et al.).
  • Activated hepatic stellate cells cause strong cell proliferation and dramatic changes in their stellate morphology, and are accompanied by lipid deposition, degradation imbalance of extracellular matrix, and over-secretion of specific marker protein, such as alpha- smooth muscle actin (a-SMA) (Schinagl et al.).
  • hepatic stellate cells migrate with the infiltrating leukocytes into damaged area of the liver (Yagai et al.), whereas inflammatory cells evoke hepatic inflammation (Wan et al.) and secret proinflammatory, as well as profibrotic factors, including transforming growth factor b1 (TGF-bI) (Zhan et al.).
  • TGF-bI transforming growth factor b1
  • Mebendazole which is an antimicrotubular agent that possesses a high affinity for tubulin, has been shown to exert an inhibitory effect on collagen bio synthesis and secretion in cell cultures (Soto et al.). These changes were reflected in an intracellular accumulation of total proteins and collagen in fibroblasts and re sult in a marked decrease of its deposit in the extracellular matrix (Soto et al.), therefore this can be directly related to hepatic stellate cells in liver disease.
  • Anoth er study in pancreatic cancer have shown a reduced connective tissue deposition and reduced a-SMA expression in samples treated with Mebendazole in compari son to untreated samples (Williamson et al.).
  • Mebendazole has the ability to reduce the levels of TGF- b1 , which is known to stimulate fibrogenesis (Guerini et al.).
  • mebendazole has also been proven to induce cytokine release from PBMC cultures. Stimulated PBMCs released several pro-inflammatory cytokines including TNFa, IL1 b, IFNy, IL6 from PBMCs activated by IL2 and anti-CD3 stimula tion (Rubin et al.). Our studies have also demonstrated that mebendazole en hanced the secretion of IL6, TNFa and IFNy ( Figures 4, 5 and 6) which is known to promote inflammation and in the long term can enhance fibrosis.
  • our strategy is to perform a combination therapy of mebendazole with Ginsenosides, as we have demonstrated that Ginsenoside has a very significant impact on the reduction of secretion of negatively impacting inflam matory cytokines, especially when high and prolonged doses are necessary.
  • fibrotic patients can benefit from Ginsenoside as it has been demon strated that it can attenuate hepatic fibrosis through regulating autophagy process es (Liu et al.).
  • Another study has demonstrated ginsenosides ability to inhibit the T ⁇ RbI/BMA ⁇ pathway, thereby improving liver fibrosis (Hafez et al.).
  • ginsenoside can induce the apoptosis of activated hepatic stellate cells (Wu et al.).
  • the present disclosure relates to a composition com prising a saponin agent, for example, ginsenoside, and an anthelmintic agent, for example mebendazole, for use in the treatment of cancer, in particular in the treat ment of solid tumors.
  • a saponin agent for example, ginsenoside
  • an anthelmintic agent for example mebendazole
  • a first aspect of the disclosure relates to a composition for use in a method of treat ing cancer, the composition comprising an effective amount of at least one saponin agent and an effective amount of at least one anthelmintic agent.
  • a first aspect of the disclosure relates to a composition for use in a method of treat ing cancer, the composition comprising an effective amount of at least one sapo-nin agent and an effective amount of at least one anthelmintic agent.
  • a second aspect relates to the composition of aspect 1 , wherein the saponin agent is a ginsenoside.
  • the ginsenoside may be an extract derived from red, black, or white ginseng, notoginseng or ginseng.
  • a third aspect relates to the composition of aspect 1 or 2, wherein the anthelmintic agent is a methyl N-(6-benzoyl- IH-benzimidazoi-2-yl)carbamate (mebendazole).
  • a fourth aspect relates to the he composition according to aspect 1 or aspect 2, wherein the anthelmintic agent is a methyl N-[6-(4-fluorobenzoyl)-1 H-benzimidazol- 2-yl]carbamate (flubendazole) and/or methyl N-(6-propylsulfanyl-1 H-benzimidazol- 2-yl)carbamate (albendazole).
  • the anthelmintic agent is a methyl N-[6-(4-fluorobenzoyl)-1 H-benzimidazol- 2-yl]carbamate (flubendazole) and/or methyl N-(6-propylsulfanyl-1 H-benzimidazol- 2-yl)carbamate (albendazole).
  • a fifth aspect relates to the composition of one of aspects 1-4, further comprising an effective amount of at least one biguanide agent, wherein the biguanide agent preferably is N,N-dimethylbiguanide (metformin).
  • the biguanide agent preferably is N,N-dimethylbiguanide (metformin).
  • a sixth aspect relates to the composition of one of aspects 1-5, wherein the com- po-sition is a nanocarrier formulation, wherein the nanocarrier preferably is PEGylat-ed or non-PEGylated.
  • a seventh aspect relates to the composition of one of aspect 6, wherein the nano- car-rier comprises SMEEDs, SNEDDS, SEDDS, solid lipid nanopartice, nanostruc- tured lipid carrier, microemulsions, liposome, micelles, polymeric nanoparticle, pol ymeric micelle, dendrimer and / or mesoporous nanoparticles, amorphous solid dis persions, solid dispersions, micronised particles, hydrogels, dendrimers, cy- clodextrins, polymer drug conjugates, iron oxide nanoparticle (magnetic carrier), gold nanoparticle
  • the nano- car-rier comprises SMEEDs, SNEDDS, SEDDS, solid lipid nanopartice, nanostruc- tured lipid carrier, microemulsions, liposome, micelles, polymeric nanoparticle, pol ymeric micelle, dendrimer and / or mesoporous nanoparticles, amorphous solid
  • An eighth aspect relates to the composition of one of aspects 1-7, wherein the cancer is selected from the group consisting of solid tumor and non-solid tumors and wherein preferably the cancer is a solid tumor selected from the group consist ing of lung cancer, liver cancer, pancreatic cancer, colorectal cancer, breast can cer, prostate cancer, brain cancer, stomach cancer, kidney cancer and cervical cancer.
  • a ninth aspect relates to the composition of one of aspects 1-8, wherein the sapon in agent, preferably a ginsenoside, is administered at an amount of from 0.001 mg/Kg body weight to 200 mg/Kg body weight, preferably from 0.01 mg/Kg body weight to 100 mg/Kg body weight, in particular from 0.1 mg/Kg body weight to 50 mg/Kg body weight (for mice and rats); and administered at an amount of from 0.001 mg/Kg body weight to 20 mg/kg body weight, preferably from 0.01 mg/Kg body weight to 15 mg/kg body weight, in particular from 0.01 mg/Kg body weight to 10 mg/kg body weight (for humans).
  • the sapon in agent preferably a ginsenoside
  • the anthelmintic agent preferably mebendazole, may also be administered at an amount of from 0.001 mg/Kg body weight to 200 mg/Kg body weight (for mice and rats); and administered at an amount of from 0.001 mg/Kg body weight to 20 mg/kg body weight (for humans) with the preferred dosage as recited above.
  • the biguanide agent preferably metformin
  • the biguanide agent may also be administered at an amount of from 0.001 mg/Kg body weight to 200 mg/Kg body weight for (mice and rats); and administered at an amount of from 0.001 mg/Kg body weight to 20 mg/kg body weight (for humans) with the preferred dosage as recited above.
  • the saponin agent, the anthelmintic agent and / or the biguanide agent may be present at the same or at different amounts in a composition according to the pre sent disclosure.
  • the saponin agent, the anthelmintic agent and /or the biguanide agent may be administered at the same or at different amounts or dosages in a me thod of treatment according to the present disclosure.
  • Saponin maybe administered at an amount of from 0.001 mg/Kg body weight to 200 mg/Kg body weight (for mice and rats); and administered at an amount of from 0.001 mg/Kg body weight to 20 mg/kg body weight (for humans) in combination with antihelmentic agent and/or biguanide agent, each preferably administered at the same range of an amount of from 0.001 mg/Kg body weight to 200 mg/Kg body weight for mice and rats); and administered at an amount of from 0.001 mg/Kg body weight to 20 mg/kg body weight (for humans).
  • Each component is preferably admi nosticered at an amount of from 0.001 mg/Kg body weight to 200 mg/Kg body weight, preferably from 0.01 mg/Kg body weight to 100 mg/Kg body weight, in par-ticular from 0.1 mg/Kg body weight to 50 mg/Kg body weight (for mice and rats); and ad ministered at an amount of from 0.001 mg/Kg body weight to 20 mg/kg body weight, preferably from 0.01 mg/Kg body weight to 15 mg/kg body weight, in partic-ular from 0.01 mg/Kg body weight to 10 mg/kg body weight (for humans).
  • a tenth aspect relates to the composition of one of aspects 1-9, wherein the effec tive amount of at least one saponin agent and the effective amount of at least one anthelmintic agent and / or the effective amount of at least one biguanide agent are present in a single formulation or are present in at least two separate formula-tions, wherein preferably the saponin agent, e.g. a ginsenoside, is administered at an amount of from 0.001 mg/Kg body weight to 200 mg/Kg body weight (for mice and rats); and administered at an amount of from 0.001 mg/Kg body weight to 20 mg/kg body weight (for humans).
  • the saponin agent e.g. a ginsenoside
  • the saponin agent is preferably administered at an amount of from 0.001 mg/Kg body weight to 200 mg/Kg body weight, preferably from 0.01 mg/Kg body weight to 100 mg/Kg body weight, in particular from 0.1 mg/Kg body weight to 50 mg/Kg body weight (for mice and rats); and administered at an amount of from 0.001 mg/Kg body weight to 20 mg/kg body weight, preferably from 0.01 mg/Kg body weight to 15 mg/kg body weight, in particular from 0.01 mg/Kg body weight to 10 mg/kg body weight (for humans).
  • the anthelmintic agent preferably mebendazole, may also be administered at an amount of from 0.001 mg/Kg body weight to 200 mg/Kg body weight for mice and rats); and administered at an amount of from tO.001 mg/Kg body weight to 20 mg/kg body weight (for humans).
  • the biguanide agent preferably metformin
  • the biguanide agent may also be administered at an amount of from 0.001 mg/Kg body weight to 200 mg/Kg body weight for (mice and rats); and administered at an amount of from 0.001 mg/Kg body weight to 20 mg/kg body weight (for humans)
  • An eleventh aspect relates to the composition of one of aspects 1-10, wherein the effec-tive amount of at least one saponin agent and the effective amount of at least one anthelmintic agent and / or the effective amount of at least one biguanide agent are administered sequentially or concurrently.
  • the present disclosure also encompasses the aspect of a method of preparation of a composition according to one of the preceding aspects.
  • Another, twelvth, aspect of the disclosure relates to a method of treating cancer, the method comprising administering to a subject in need thereof an effective amount of at least one saponin agent and an effective amount of at least one an-thelmintic agent.
  • the saponin agent and the anthelmintic agent can be administered simultaneous-ly or sequentially and / or can be administered in a single composition or multiple se parate compositions.
  • the subject is preferably human.
  • the cancer can be a cancer comprising cancer stem cells.
  • the saponin agent is a ginsenoside.
  • a fourteenth aspect relates to a method according to one of aspects 12 or 13, wherein the anthelmintic agent is a methyl N-(6-benzoyl- IH-benzimidazoi-2- yl)carbamate (mebendazole).
  • a fifteenth aspect relates to a method according to one of aspects 12 to 14, wherein the method further comprises administering to the subject an effective amount of at least one biguanide agent, wherein the biguanide agent is N,N- dimethylbiguanide (metformin).
  • a sixteenth aspect relates to a method according to one of aspects 12 to 15, whe- re-in the composition is a nanocarrier formulation, wherein the nanocarrier prefe rably is PEGylated or non-PEGylated.
  • a eventeenth aspect relates to a method according to one of aspect 16, wherein the nanocarrier comprises SMEEDs, SNEDDS, SEDDS, solid lipid nanopartice, nanostructured lipid carrier, microemulsions, liposome, micelles, polymeric nano particle, polymeric micelle, dendrimer and / or mesoporous nanoparticles, amor phous solid dispersions, solid dispersions, micronized particles, hydrogels, den- drimers, cyclodextrins, polymer drug conjugates, iron oxide nanoparticle (magnetic carrier), gold nanoparticle
  • the composition may be administered orally, e.g. as a pill or liquid, or the composition may be injected into a subject.
  • a eighteenth aspect relates to a method according to one of aspects 12 to 17, wherein the cancer is selected from the group consisting of solid tumor and non solid tumors and wherein preferably the cancer is a solid tumor selected from the group consisting of lung cancer, liver cancer, pancreatic cancer, colorectal cancer, breast cancer, prostate cancer, brain cancer, stomach cancer, kidney cancer and cervical cancer.
  • the cancer is selected from the group consisting of solid tumor and non solid tumors and wherein preferably the cancer is a solid tumor selected from the group consisting of lung cancer, liver cancer, pancreatic cancer, colorectal cancer, breast cancer, prostate cancer, brain cancer, stomach cancer, kidney cancer and cervical cancer.
  • the cancer can also be oral cancer, liver cancer, stomach cancer, colon cancer, breast cancer, lung cancer, bone cancer, pancreatic cancer, skin cancer, head cancer, cervical cancer, skin cancer, cervical cancer, ovarian cancer, colon cancer, small intestine cancer, rectal cancer, fallopian tube carcinoma, anal muscle can-cer, uterus endocrine carcinoma, vaginal carcinoma, vulvar carcinoma, Hodgkin's dise ase, esophageal cancer, lymph adenocarcinoma, bladder cancer, gallbladder cancer, endocrine cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic Any one or more selected from the group consisting of leukemia, acute leukemia, lympho-cytic lymphoma, kidney cancer, ureteral cancer, renal cell carcinoma, renal pelvic carci noma, central nervous system tumor, primary central nervous system lym-phoma, spinal cord tumor, brain stem glioma
  • a ninteenth aspect relates to a method according to one of aspects 12 to 18, wherein the saponin agent, preferably a ginsenoside, is administered at an amount of from 0.001 mg/Kg body weight to 50 mg/Kg body weight.
  • the anthelmin-tic agent preferably mebendazole, may also be administered at an amount of from 0.001 mg/Kg body weight to 50 mg/Kg body weight.
  • the biguanide agent preferably metformin, may also be administered at an amount of from 0.001 mg/Kg body weight to 50 mg/Kg body weight.
  • a twentieth aspect relates to a method according to one of aspects 12 to 19, wherein the effective amount of at least one saponin agent and the effective amount of at least one anthelmintic agent and / or the effective amount of at least one biguanide agent are administered in a single formulation or in at least two se parate formulations.
  • a twenty-first aspect relates to a method according to one of aspects 12 to 20, where-in the effective amount of at least one saponin agent and the effective amount of at least one anthelmintic agent and / or the effective amount of at least one bigua-nide agent are administered sequentially or concurrently.
  • Another, twenty-secondt, aspect of the present disclosure relates to a use of an effec-tive amount of at least one saponin agent and an effective amount of at least one anthelmintic agent and / or an effective amount of at least one biguanide agent in the preparation of a composition for the treatment of cancer.
  • a twenty-third aspect relates to a use according to aspect 22, wherein the sapo-nin agent is a ginsenoside.
  • a twenty-fourth aspect relates to a use according to aspect 22 or 23, wherein the anthelmintic agent is a methyl N-(6-benzoyl- IH-benzimidazoi-2-yl)carbamate (me bendazole).
  • the anthelmintic agent can be flubendazole or albendazole.
  • a twenty-fifth aspect relates to a use according to one of aspects 22 to 24, wherein the biguanide agent is N,N-dimethylbiguanide (metformin).
  • the biguanide agent is N,N-dimethylbiguanide (metformin).
  • kits for treating cancer preferably a solid tumor, in a human subject
  • the kit comprising a composition com prising an effective amount of at least one saponin agent and an effective amount of at least one anthelmintic agent and / or an effective amount of at least one bigu anide agent, and instructions for use.
  • a twenty-seventh aspect of the disclosure relates to a kit according to aspect 26, wherein the effective amount of at least one saponin agent and the effective amount of at least one anthelmintic agent and / or the effective amount of at least one biguanide agent are present in a single formulation or are present in at least two separate formulations.
  • a twenty-eighth aspect of the disclosure relates to a method for treating cancer comprising administering to a subject in need thereof (a) an effective amount of at least one saponin agent and (b) an effective amount of at least one anthelmintic agent to provide a combination therapy having enhanced therapeutic effect and / or reduced side effects compared to the effect of the saponin agent and the an thelmintic agent each administered alone.
  • a twenty-nineth aspect of the disclosure relates to a method for treating cancer comprising administering to a subject in need thereof (a) an effective amount of at least one saponin agent and (b) an effective amount of at least one biguanide agent to provide a combination therapy having enhanced therapeutic effect and / or reumbled side effects compared to the effect of the saponin agent and the bigua-nide agent each administered alone.
  • the biguanide agent may be administered in com bination with the saponin agent and the anthelmintic agent according to the twenty- eighth aspect.
  • a thirtieth aspect of the disclosure relates to the composition according to one of the preceding aspects, further comprising an effective amount of at least one anti fungal agent, wherein the antifungal agent preferably is (R-(R*,S*))-alpha-(2,4- difluorophenyl)-5-fluoro-beta-methyl-alpha-(1 H-1 ,2,4-triazoM -ylmethyl)-4- pyrimidineethanol(aR,pS)-a-(2,4-difluorophenyl)-5-fluoro-p-methyl-a(1 H-1 ,2,4- triazol-1-ylmethyl)-4-pyrimidineethanol (Voriconazole), and/or, 4-[4-[4-[4-[4-[[[(3R,5R)- 5-(2,4-difluorophenyl)-5-(1 ,2,4-triazoM -ylmethyl)oxolan-3- yl]methoxy]
  • a thirty-first aspect of the disclosure relates to the composition according to one of the preceding aspects, wherein the composition further comprises a bioavailability enhancer, wherein the bioavailability enhancer is a CYP inhibitor and/or a drug transport inhibitor.
  • a thirty-second aspect of the disclosure relates to the composition according to one of the preceding claims for use in a method of treating liver disease, wherein the liver disease is selected from the group consisting of alcohol-related liver disease, non-alcoholic fatty liver disease, hepatitis, primary biliary cirrhosis and/or liver fibro sis.
  • compositions or compositions disclosed herein for the treat- mnent of liver dieases are preferably based on the mechanism of action described in the the present application. There is thus a plausible mechanism of action proposed herein supporting the effect of the claimed compositions in the treatment of liver diseases. Further experiments relating thereto are being performed.
  • present disclosure is not limited to the features or aspects of the invention as described above, but also encompasses any such feature or aspect in isolation as well as any combination of features or aspects described above.
  • the lung A549, colon HCT 116, breast MDA-MB-231, pancreas PANC1 and liver FlepG2 tumor cell line were used as target in the immune cell-mediated kill-ing as say described below.
  • a solid tumor selected from the group consisting of lung cancer, liver cancer, pancreatic cancer, colorectal cancer, breast cancer, prostate cancer, brain cancer, stomach cancer, kidney cancer and cervical cancer, oral cancer, stomach cancer, colon cancer, bone cancer, pancreatic cancer, skin cancer, head cancer, skin cancer, ovarian cancer, small intestine cancer, rectal cancer, fallopian tube carcinoma, anal muscle cancer, uterus Endocrine carcinoma, vaginal carcinoma, vulvar carci-noma, Flodgkin's disease, esophageal cancer, lymph adenocarcinoma, bladder cancer, gallbladder cancer, endocrine cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chro nic leukemia, acute leukemia, lymphocytic lymphoma, kidney cancer, ure-teral cancer
  • MDA-MB-231 Breast cancer cell line (BRAF mutant, CDKN2A mutant, K-RAS mu tant, TP53 mutant)
  • HCT1 16 Colon cancer cell line (K-RAS mutant, PIK3CA mutant)
  • PANC-1 Pancreatic cancer cell line K-RAS mutant, TP53 mutant, CDKN2A mu tant
  • HepG2 Liver cancer cell line (CTNNB1 mutant, TERT mutant, NRAS mutant)
  • Test compound treatment Tested compounds were directly ordered from their Provider, received in powder form and stored at their respective appropriate tem-peratures. Compounds were resuspended according to their respective ap limbate conditions. Each of the three compounds were tested at one dose (+ the 0 ; 10mM for R848 ; 50mM for Ginsenoside Rh2, IOOOmM for Metformin and 1mM for Meben-dazole), each alone, in combination of two then in combination of three (as de-tailed below). Compound treatments were applied at the time of tumor- immune cell co-culture initiation, in parallel with the addition of the human effector immune cells.
  • A549 human lung carcinoma cell line modified to ex-press a nuclear fluorescent probe
  • A549 human lung carcinoma cell line modified to ex-press a nuclear fluorescent probe
  • Positive control e.g. Atezolizumab at 1 dose
  • Ginsenoside Rh2 50uM+Mebendazole (1uM)+Metformin (IOOOuM) R848 (1 OuM)+Mebendazole (1 uM)+Metformin (1 OOOuM)
  • Tumor cell proliferation and apoptosis were followed by live cell imaging (ba sed on a nuclear fluorescence and apoptosis specific fluorescence probes).
  • live cell imaging ba sed on a nuclear fluorescence and apoptosis specific fluorescence probes.
  • supernatants from immune / tumor cell co-cultures were retrieved 72h after co culture initiation & treatment for the quantification of the IFNg, TNFa and IL-6 re leased levels, as surrogates of immune cell activation/activity.
  • Image acquisition started 24h after tumor cell seeding, when the treatment with test compounds was applied (at the tumor- immune cell co-culture initiation). Phase contrast, green channel (fluorescent caspase3/7 apoptosis probe) and red channel (fluorescent tumor nuclear probe) images were acquired on an IncuCyte ZOOMTM Live cell imager using a 10x objec tive, with 1 image every 3-4 hours for 5 days monitoring period.
  • Image analysis we re performed using IncuCyte ZOOMTM software following application of a seg mentation mask analysis on phase contrast images to identify cell surface, on red fluorescence images to select tumor cells (expressing the red fluorescent nuclear probe) and on green fluorescence images to identify apoptotic cells (Caspase 3/7 probe ; DEVD-NucViewTM488).
  • Overlay segmentation analysis was applied to iden tify apoptotic tumor cells. Data were analyzed and plotted using Graph Pad Prism v6.01 software.
  • IFNg, TNFa and IL-6 quantificati on were performed using specific HTRF-based detection kits (TECAN Infinite F500 microplate reader).
  • Test compound treatment Tested compounds were directly ordered from their Provider, received in powder form and stored at their respective appropriate temperatures. Compounds were resuspended according to their respective approp riate conditions. Each of the three compounds were tested at one dose (+ the 0; 50mM for Ginsenoside Rh2 and 1mM for Mebendazole), each alone or in combinati on. Compound treatments were applied at the time of tumor- immune cell co-culture initiation, in parallel with the addition of the human effector immune cells.
  • MDA-MB-231 HCT-116, PANC-1 or HepG2 tumor killing assay.
  • MDA-MB-231, HCT-116, PANC-1 and HepG2 tumor cells modified to express a nuclear flu orescent probe, were seeded at an appropriate cell density and cultured for 24h, before being co-cultured - at the E:T ratio of 10:1 - with human effector immune cells (a healthy donor-originating PBMCs) activated with anti-CD3 antibody (2 do ses including the 0: 0 and 0.05pg/ml_), and submitted to the treatment conditions below :
  • Tumor cell proliferation and apoptosis were followed by live cell imaging (ba sed on a nuclear fluorescence and apoptosis specific fluorescence probes).
  • live cell imaging ba sed on a nuclear fluorescence and apoptosis specific fluorescence probes.
  • supernatants from immune / tumor cell co-cultures were retrieved 72h after co culture initiation & treatment for the quantification of the TNFa and IL-6 released levels, as surrogates of immune cell activation/activity.
  • Image acquisition started 24h after tumor cell seeding, when the treatment with test compounds was applied (at the tumor- immune cell co-culture initiation). Phase contrast, green channel (fluorescent caspase3/7 apoptosis probe) and red channel (fluorescent tumor nuclear probe) images were acquired on an IncuCyte ZOOMTM Live cell imager using a 10x objec tive, with 1 image every 3-4 hours for 5 days monitoring period.
  • Image analysis we re performed using IncuCyte ZOOMTM software following application of a seg mentation mask analysis on phase contrast images to identify cell surface, on red fluorescence images to select tumor cells (expressing the red fluorescent nuclear probe) and on green fluorescence images to identify apoptotic cells (Caspase 3/7 probe ; DEVD-NucViewTM488).
  • Overlay segmentation analysis was applied to iden tify apoptotic tumor cells. Data were analyzed and plotted using Graph Pad Prism v6.01 software.
  • TNFa and IL-6 quantification were perfor med using specific HTRF-based detection kits (TECAN Infinite F500 microplate reader).
  • Fig. 3d Enhanced killing of cancer cells were demonstrated after exposure with ginseno-side and mebendazole and after exposure with ginsenoside and metformin.
  • tumor cell count reached zero or a negligible level between 96-120 after exposure with ginsenoside and mebendazole and after exposure with gin senoside and metformin (Fig. 3b).
  • IL-6 is also known to be a surrogate of immune response, inflammation, tu mor progression and pain. Serum IL-6 is associated with worse prognosis and poor survival in cancer patients.
  • Tocilizumab Anti IL-6 Receptor antibody
  • Targeting IL-6 pathway does not activate tumor progression.
  • Ginsenoside and Mebendazole trigger a im- mune-mediated tumor cell killing without the secretion of IL-6 and Therefore, Ginseno-side and Mebendazole combination reduces IL-6 cytokine release com monly associat-ed with cancer cachexia, physical and neuropathic pain, fatigue and poor quality of life.
  • cytokine release modu lations were observed both in the condition of activated and non-activated PBMCs, but differed, interestingly, depending on the treatment and on the intended cytokine. o Indeed IFNg released levels (Figure 4) were demonstrated to be modula ted, more strongly, in the configuration of activated PBMCs. While mebendazole was shown to partially decrease IFNg levels in the supernatants, metformin and Gin-senoside showed a complete inhibition.
  • R848 was shown to induce an increase in the IFNg amount when applied alone, an effect which seemed to be (i) partially and (ii) completely “antagonized” by (i) mebendazole and (ii) metformin or Ginsenoside Rh2. o
  • TNFa levels Figure 5
  • R848 shows an increase in the released cytoki ne, which was inhibited by metformin but not by mebendazole.
  • IL-6 release increased in co-cultures with inactivated PBMCs and even more with activated PBMCs. In both cases, IL-6 levels were shown to be slightly optimized by Atezolizumab.
  • FIG. 1 Real-time live cell monitoring of PBMCs, with and without anti-CD3 activation, in the presence and absence of Atezolizumab.
  • PBMCs were cultured in the presence and absence of aCD3 and in the presence and absence of Atezolizumab (1ug/mL).
  • Cell conflu ence was monitored and quantified over a period of ⁇ 5 days, as a surrogate measure of immune cell proliferation. Data were normalized and corrected to the baseline and are ex pressed as means ⁇ SEM.
  • FIG. 2 Real-time live cell monitoring of lung A549 tumor cell killing mediated by acti vated PBMCs, under untreated and Atezolizumab-treated conditions.
  • Lung A549 tumor cells were seeded and 24h later were co-cultured with activated PBMCs, in the presence and absence of aCD3, in the presence and absence of Atezolizumab (1ug/mL).
  • Tumor cell count (A) and apoptosis (B) were monitored and quantified over a period of ⁇ 5 days, by mean of a NucRed probe expression and caspase 3/7 fluorescent probe, respectively, as surrogate measures of immune cell killing activity towards tumor cells.
  • Apoptosis is repre sented as an index evaluated with respect to the apoptosis events and cell number in each condition. Data were normalized and corrected to the baseline and are expressed as means ⁇ SEM.
  • FIG. 3 Real-time live cell monitoring of lung A549 tumor cell killing mediated by activat ed PBMCs, under treatment with test compounds.
  • Lung A549 tumor cells were seeded and 24h later were co-cultured with activated PBMCs, in the presence and absence of aCD3 (Oug/mL (a, c) and 0,05ug/mL (b, d)), under the different conditions of treatments with compounds.
  • Tumor cell count (A (a, b)) and apoptosis (B (c, d)) were monitored and quan tified over a period of ⁇ 5 days, by mean of a NucRed probe expression and caspase 3/7 fluorescent probe, respectively, as surrogate measures of immune cell killing activity to wards tumor cells.
  • Apoptosis is represented as an index evaluated with respect to the apoptosis events and cell number in each condition. Data were normalized and corrected to the baseline and are expressed as means ⁇ SEM.
  • FIG. 4 IFNy levels in culture supernatants after 72h post co-culture initiation, measured by HTRF-based technology on TECAN Spark microplate reader. IFNy levels released in the supernatants of activated PBMC in the presence of aCD3 (applied at 2 doses - 0 and 0,05ug/mL), cultured either alone (left part) or in co-culture for 72h with A549 tumor cells under the different conditions of treatments with compounds or with Atezolizumab 1ug/mL (right part). Data were represented as mean ⁇ SEM.
  • FIG. 5 TNFa levels in culture supernatants after 72h post co-culture initiation, measured by HTRF-based technology on TECAN Spark microplate reader. TNFa levels released in the supernatants of activated PBMC in the presence of aCD3 (applied at 2 doses - 0 and 0,05ug/mL), cultured either alone (left part) or in co-culture for 72h with A549 tumor cells under the different conditions of treatments with compounds or with Atezolizumab 1ug/mL (right part). Data were represented as mean ⁇ SEM.
  • Figure 6 IL6 levels in culture supernatants after 72h post co-culture initiation, measured by HTRF- based technology on TECAN Spark microplate reader. IL6 levels released in the supernatants of activated PBMC in the presence of aCD3 (applied at 2 doses - 0 and 0,05ug/mL), cultured either alone (left part) or in co-culture for 72h with A549 tumor cells under the different conditions of treatments with compounds or with Atezolizumab 1ug/mL (right part). Data were represented as mean ⁇ SEM.
  • FIG. 7 Real-time live cell monitoring of lung A549, breast MDA-MB-231, colon HCT116, Pancreatic PANC1, liver HEPG2 tumor cell killing mediated by inactivate and activated PBMCs, under untreated and treated test compounds.
  • the respective tumor cells were seeded and 24h later were co-cultured with PBMCs, in the absence (inactive; top graphs) and presence (activated with 0.05 ug/mL CD3+; bottom graphs) under the different condi tions of treatments with compounds.
  • Tumor cell count were monitored and quantified over a period of ⁇ 5 days, by mean of a NucRed probe expression and caspase 3/7 fluorescent probe, respectively, as surrogate measures of immune cell killing activity towards tumor cells. Data were normalized and corrected to the baseline and are expressed as means ⁇ SEM.
  • FIG. 8 The synergistic cell killing effect of mebendazole combined with Ginsenoside on the growth of lung A549, breast MDA-MB-231, colon HCT116, Pancreatic PANC1, liver HEPG2 tumor mediated by activated PBMCs.
  • a CDI ⁇ 1 ndicates synergism, CDI 1 indicates additivity and CDI >1 indicates antagonism.
  • a CDI value less than 0.7 indicates that the drugs are significantly synergistic.
  • Our combination therapy produced a CDI of zero in all cancer cell types, which is the strongest possible indication of synergy.
  • Figure 9 IL-6 levels in activated PBMC and tumor cell co-culture supernatants of lung A549, breast MDA-MB-231, colon HCT116, pancreas PANC1 and liver HEPG2 tumour cells after 72h post co-culture initiation, measured by HTRF-based technology on TECAN Spark microplate reader IL-6 levels in culture supernatants after 72h post co-culture initia tion, measured by HTRF-based technology on TECAN Spark microplate reader.
  • IL-6 levels released in the supernatants of activated PBMC CD3+ at (0.05 ug/mL) with cancer cells when left untreated (yellow bars), treated with Ginsenoside Rh2 (50uM; blue bars), treated with Mebendazole (1uM; green bars) or treated with both Ginsenoside Rh2 and Meben dazole (50uM and 1uM; red bars).

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Abstract

La présente invention concerne une composition destinée à être utilisée dans une méthode de traitement du cancer, la composition comprenant une quantité efficace d'au moins un agent à base de saponine, de préférence du ginsénoside, et une quantité efficace d'au moins un agent anthelminthique, de préférence le mébendazole. La composition peut également être utilisée dans le traitement de maladies hépatiques.
EP22733921.5A 2021-06-11 2022-06-10 Polythérapie à base d'un agent de saponine et d'un agent anthelmintique contre le cancer Pending EP4351572A1 (fr)

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US6693125B2 (en) * 2001-01-24 2004-02-17 Combinatorx Incorporated Combinations of drugs (e.g., a benzimidazole and pentamidine) for the treatment of neoplastic disorders
WO2004056379A1 (fr) * 2002-12-23 2004-07-08 Panagin Pharmaceuticals Inc. Saponines et sapogenines a utiliser en combinaison avec une therapie anticancereuse
WO2010135534A2 (fr) * 2009-05-20 2010-11-25 Children's Medical Center Corporation Compositions pour le traitement du cancer metastatique et leurs procedes d'utilisation
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WO2017123056A1 (fr) * 2016-01-14 2017-07-20 경희대학교 산학협력단 Nanocomposite comprenant un système d'administration de médicament nanométrique et extrait de ginseng ou ginsénoside séparé de celui-ci
US20190175560A1 (en) * 2017-12-01 2019-06-13 Shepherd Therapeutics, Inc. Mebendazole cancer therapies and methods of use
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