Patent Description:
Many attempts to treat malignant neoplastic cells through conventional therapies have been met with limited success due to inter- and intra-tumor heterogeneity within the mosaic of tumor subclones. For example, <CIT> discloses a cancer drug. Further prior art is the publication by <NPL>.

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 targets) resistant to such treatments.

Moreover, some tumor 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 subclones, particularly under increased selective pressures of survival, thus certain emerging subclones will develop increased resistance to chemotherapy and molecular targeted therapy which will further progress to aggressive tumor progression, worse prognosis and poor survival.

From a patient point of view, 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-<NUM>-TRPA1 and TNF-alpha-TRPA1 pathways (Liu et al. Blocking IL-<NUM> and TNF-alpha was shown to be beneficial in inhibiting pain in in-vivo models including chemotherapy-induced pain.

Thus, of great interest, was the paradigm shift towards antigen-independent immuno-oncology for cancer treatment to concurrently target different subclones of the heterogenous tumor mosaic simultaneously.

However, despite efforts of non-antigen specific immune-oncology (particularly immune checkpoint inhibitors ICIs) showing promise in achieving partial and even some complete responses in can-cer patients, a high risk of autoimmune-like immune related adverse events (iRAEs) 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 (König & Läubli, <NUM>). Post-mortem studies showed that melanoma cancer patients receiving ICIs led to immune infiltration in the myocardial tissue which developed into myocarditis (Gürdo<IMG>an, <NUM>).

Among the most common inflammatory cytokines as biomarkers of iRAEs is IL-<NUM> which is also known to be a surrogate of immune response, inflammation, tumor progression and pain. Serum IL-<NUM> is associated with worse prognosis and poor survival in cancer patients.

Among the first treatments of iRAEs such severe arthri-tis, myocarditis, uveitis, great vasculitis, severe pneumonia, great vasculitis, and myasthenia gravis is Tocilizumab (Anti IL-<NUM> Receptor antibody) which inhibits IL-<NUM> signalling. Targeting IL-<NUM> pathway does not activate tumor progression.

Therefore, tumor cell killing without triggering IL-<NUM> and/or activate IL-<NUM> signalling pathways and other inflammatory cytokines pose as great benefit for patients 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 non-inflammatory, antigen independent immune-mediated tumor cell killing without the secretion of IL-<NUM> and TNF-alpha. Therefore, Ginsenoside and Mebendazole in combination reduce cytokine release commonly associated with cancer cachexia, physical and neuropathic pain, fatigue 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 <NUM> and caspase <NUM>/<NUM> activation downstream.

Additionally, activated caspase <NUM> could also indirectly activate caspase <NUM>/<NUM> by truncating BID, a pro-apoptotic protein, into its functional form tBID; tBID then contributes to translocating BAX to the mitochondria to re-lease mitochondrial cytochrome c thus triggering intrinsic apoptosis as well.

With respect to extrinsic apoptosis, tumors generally live in harsh pathophysiological conditions such as low glucose and hypoxia which trigger intracellular ER stress and impairment in protein folding, lipid metabolism and calcium level regulation. 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. , <NUM>; Martín-Pérez et al.

However, there are several TRAIL-resistant cancer cells which are due to increased pro-survival anti-apoptotic proteins. Nevertheless, these resistant cells are sensitized to apoptosis upon inhibition of the pro-survival Akt- pathway (commonly expressed in many tumors) inhibition resulting in a de-crease of pro-survival proteins (such as Bcl-<NUM> and BcL-xL) compared to pro-apototic counterparts (BAX).

Akt also phosphorylates BAX at Serine <NUM> 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 signalling pathways). This inactivates the pro-surivival Akt pathway and helps to rapidly and strongly translocate BAX into the mitochondria, thus further triggering mitochondrial-based intrinsic apoptosis.

To further sensitise TRAIL apoptosis, three strategies could be approached: (i) By further decreasing pro-survival proteins in tumors through further inhibition of pro-survival proteins. (ii) By increasing TRAIL-ligand expression in cells surrounding tumors, by enhancing immune activation. (iii) Convert non-immunological 'cold' tumors to immune-infiltrative hot tumors.

Mebendazole, an anti-helminth drug, addresses the three strategies above by (i) phosphorylating and deactivating BCL-<NUM> protein, (ii) enhance T-cell activation through increased clustering and interaction between CD14+monocytes/macrophages and T-cells and (iii) re-polarize immunosuppressive tumor-promoting M2 macrophages to M1 classically activated antitumor macrophages which can directly kill the tumor and provide chemokine signals to increase immune infiltration of activated immune cells expressing TRAIL could interact with TRAIL-sensitized tumor cells to induce cancer cell death.

Hence in summary, antigen-independent tumor cell death is based on extrinsic death receptor-based and intrinsic mitochondrial-based apoptotic pathways, suggestively 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.

Rather than systemically targeting highly proliferative cells which results in off-target toxicities, such as chemotherapy-induced alopecia, selective tumor cell killing based upon cross-sectional ER stress-based apoptotic pathways among different tumors.

This provides a strategy to selectively target different malignant cells of different tissue origins while keeping physiologically unstressed cells intact and non-targeted, particularly hair follicles of cancer patients.

Our studies also incorporate immune mediated tumor cell killing in cancer cell lines that harbor other very common oncogenic mutations such as:.

The present invention relates to a composition comprising a saponin agent, namely ginsenoside, and an anthelmintic agent, namely mebendazole, for use in the treatment of cancer, in particular in the treatment of solid tumors.

In the following, aspects of the present disclosure are described that may be realised individually or in combination in an embodiment or embodiments of the present invention.

A first aspect of the invention relates to a composition for use in a method of treating cancer, the composition comprising an effective amount of at least one saponin agent and an effective amount of at least one anthelmintic agent, wherein the saponin agent is a ginsenoside and the anthelmintic agent is a methyl N-(<NUM>-benzoyl-<NUM>-benzimidazol-<NUM>-yl)carbamate (mebendazole).

A second aspect relates to the composition of aspect <NUM>, further comprising an effective amount of at least one biguanide agent, wherein the biguanide agent preferably is N,N-dimethylbiguanide (metformin).

A third aspect relates to the composition of one of aspects <NUM>-<NUM>, wherein the composition is a nanocarrier formulation, wherein the nanocarrier preferably is PEGylat-ed or non-PEGylated.

A fourth aspect relates to the composition of one of aspect <NUM>, wherein the nanocarrier 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 dispersions, solid dispersions, micronised particles, hydrogels, dendrimers, cy-clodextrins, polymer drug conjugates, iron oxide nanoparticle (magnetic carrier), gold nanoparticle.

A fifth aspect relates to the composition of one of aspects <NUM>-<NUM>, 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.

An sixth aspect relates to the composition of one of aspects <NUM>-<NUM>, wherein the saponin agent, namely a ginsenoside, is administered at an amount of from <NUM>/Kg body weight to <NUM>/Kg body weight, preferably from <NUM>/Kg body weight to <NUM>/Kg body weight, in particular from <NUM>/Kg body weight to <NUM>/Kg body weight (for mice and rats); and administered at an amount of from <NUM>/Kg body weight to <NUM>/kg body weight, preferably from <NUM>/Kg body weight to <NUM>/kg body weight, in particular from <NUM>/Kg body weight to <NUM>/kg body weight (for humans).

The anthelmintic agent, namely mebendazole, may also be administered at an amount of from <NUM>/Kg body weight to <NUM>/Kg body weight (for mice and rats); and administered at an amount of from <NUM>/Kg body weight to <NUM>/kg body weight (for humans) with the preferred dosage as recited above.

Similarly, the biguanide agent, preferably metformin, may also be administered at an amount of from <NUM>/Kg body weight to <NUM>/Kg body weight for (mice and rats); and administered at an amount of from <NUM>/Kg body weight to <NUM>/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 present 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 method of treatment according to the present disclosure.

Saponin maybe administered at an amount of from <NUM>/Kg body weight to <NUM>/Kg body weight (for mice and rats); and administered at an amount of from <NUM>/Kg body weight to <NUM>/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 <NUM>/Kg body weight to <NUM>/Kg body weight for mice and rats); and administered at an amount of from <NUM>/Kg body weight to <NUM>/kg body weight (for humans). Each component is preferably administered at an amount of from <NUM>/Kg body weight to <NUM>/Kg body weight, preferably from <NUM>/Kg body weight to <NUM>/Kg body weight, in particular from <NUM>/Kg body weight to <NUM>/Kg body weight (for mice and rats); and administered at an amount of from <NUM>/Kg body weight to <NUM>/kg body weight, preferably from <NUM>/Kg body weight to <NUM>/kg body weight, in particular from <NUM>/Kg body weight to <NUM>/kg body weight (for humans).

A seventh aspect relates to the composition of one of aspects <NUM>-<NUM>, wherein the effective amount of at least one saponin agent, namely ginsenoside, and the effective amount of at least one anthelmintic agent, namely mebendazole, 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, wherein preferably the saponin agent, i.e. the ginsenoside, is administered at an amount of from <NUM>/Kg body weight to <NUM>/Kg body weight (for mice and rats); and administered at an amount of from <NUM>/Kg body weight to <NUM>/kg body weight (for humans). The saponin agent is preferably administered at an amount of from <NUM>/Kg body weight to <NUM>/Kg body weight, preferably from <NUM>/Kg body weight to <NUM>/Kg body weight, in particular from <NUM>/Kg body weight to <NUM>/Kg body weight (for mice and rats); and administered at an amount of from <NUM>/Kg body weight to <NUM>/kg body weight, preferably from <NUM>/Kg body weight to <NUM>/kg body weight, in particular from <NUM>/Kg body weight to <NUM>/kg body weight (for humans).

The anthelmintic agent, i.e. mebendazole, may also be administered at an amount of from <NUM>/Kg body weight to <NUM>/Kg body weight for mice and rats); and administered at an amount of from t0. <NUM>/Kg body weight to <NUM>/kg body weight (for humans).

Similarly, the biguanide agent, preferably metformin, may also be administered at an amount of from <NUM>/Kg body weight to <NUM>/Kg body weight for (mice and rats); and administered at an amount of from <NUM>/Kg body weight to <NUM>/kg body weight (for humans).

A eighth aspect relates to the composition of one of aspects <NUM>-<NUM>, wherein the effective amount of at least one saponin agent, i.e. ginsenoside, and the effective amount of at least one anthelmintic agent, i.e. mebendazole, 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, nineth, 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, namely ginsenoside, and an effective amount of at least one anthelmintic agent, namely mebendazole.

The saponin agent and the anthelmintic agent can be administered simultaneously or sequentially and / or can be administered in a single composition or multiple separate compositions.

The subject is preferably human. The cancer can be a cancer comprising cancer stem cells.

A tenth aspect relates to a method according to aspect <NUM>, 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).

An eleventh aspect relates to a method according to one of aspects <NUM> to <NUM>, wherein the composition is a nanocarrier formulation, wherein the nanocarrier preferably is PEGylated or non-PEGylated.

A twelth aspect relates to a method according to one of aspect <NUM>, wherein the nanocarrier comprises SMEEDs, SNEDDS, SEDDS, solid lipid nanopartice, nanostructured lipid carrier, microemulsions, liposome, micelles, polymeric nanoparticle, polymeric micelle, dendrimer and / or mesoporous nanoparticles, amorphous solid dispersions, solid dispersions, micronized particles, hydrogels, dendrimers, cyclodextrins, polymer drug conjugates, iron oxide nanoparticle (magnetic carrier), gold nanoparticle.

In principle, the composition may be administered orally, e.g. as a pill or liquid, or the composition may be injected into a subject.

A thirteenth aspect relates to a method according to one of aspects <NUM> to <NUM>, 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. This list, however, is only exemplary and does not serve to limit the present disclosure.

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 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, 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 carcinoma, central nervous system tumor, primary central nervous system lym-phoma, spinal cord tumor, brain stem glioma, and pituitary adenoma.

A fourteenth aspect relates to a method according to one of aspects <NUM> to <NUM>, wherein the saponin agent, i.e. a ginsenoside, is administered at an amount of from <NUM>/Kg body weight to <NUM>/Kg body weight. The anthelmin-tic agent, preferably mebendazole, may also be administered at an amount of from <NUM>/Kg body weight to <NUM>/Kg body weight. Similarly, the biguanide agent, preferably metformin, may also be administered at an amount of from <NUM>/Kg body weight to <NUM>/Kg body weight.

A fifteenth aspect relates to a method according to one of aspects <NUM> to <NUM>, 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 separate formulations.

A sixteenth aspect relates to a method according to one of aspects <NUM> to <NUM>, wherein the effective amount of at least one saponin agent, namely ginsenoside, and the effective amount of at least one anthelmintic agent, namely mebendazole, and / or the effective amount of at least one biguanide agent are administered sequentially or concurrently.

Another, sevententh, aspect of the present disclosure relates to a use of an effective amount of at least one saponin agent, i.e. ginsenoside, and an effective amount of at least one anthelmintic agent, i.e. mebendazole, and / or an effective amount of at least one biguanide agent in the preparation of a composition for the treatment of cancer.

An eighteenth aspect relates to a use according to aspect <NUM>, wherein the biguanide agent is N,N-dimethylbiguanide (metformin).

Another, nineteenth, aspect of the disclosure relates to a kit for treating cancer, preferably a solid tumor, in a human subject, the kit comprising a composition comprising an effective amount of at least one saponin agent, namely ginsenoside, and an effective amount of at least one anthelmintic agent, namely mebendazole, and / or an effective amount of at least one biguanide agent, and instructions for use.

A twentieth aspect of the disclosure relates to a kit according to aspect <NUM>, 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-first 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, namely ginsenoside, and (b) an effective amount of at least one anthelmintic agent, namely mebendazole, 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-second 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, namely ginsenoside, and (b) an effective amount of at least one biguanide agent, namely mebendazole, to provide a combination therapy having enhanced therapeutic effect and / or reduced side effects compared to the effect of the saponin agent and the biguanide agent each administered alone. The biguanide agent may be administered in combination with the saponin agent and the anthelmintic agent according to the twenty-eighth aspect.

The 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 disclosure is further illustrated by exemplary experimental data that are discussed in the following section. Further features, effects and advantageous become apparent from the following discussion referring to <FIG>.

The following in vitro study was performed in order to evaluate a new array of treatment conditions, including the TLR7/<NUM> agonist (R848), metformin - an antihyperglycemic agent which impairs cellular metabolism (and can thus suppress oncogenic signaling pathways including PI3K/Akt and mTOR signaling pathways), and mebendazole (anti-helminthic agent), for their ability to enhance the killing ability of immune cells towards tumor cells.

The lung A549 tumor cell line was used as target in the immune cell-mediated killing assay described below.

Further experiments are being performed following the same or a highly similar experimental protocol as described in the following section using cell lines from a solid tumor selected from the group consisting of lung cancer, liver cancer, pan-creatic 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 can-cer, ovarian cancer, small intestine cancer, rectal cancer, fallopian tube carcinoma, anal muscle cancer, uterus Endocrine carcinoma, vaginal carcinoma, vulvar carci-noma, Hodgkin'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, chronic leukemia, acute leukemia, lymphocytic lymphoma, kidney cancer, ure-teral cancer, renal cell carcinoma, renal pelvic carcinoma, central nervous system tumor, primary central nervous system lymphoma, spinal cord tumor, brain stem glioma, and pituitary adenoma as well as cell lines of non-solid cancers.

For example, the same or similar in vitro studies are being performed on the following non-limiting list of cell lines:.

The in vitro study disclosed herein aimed at evaluating the effects of several treatment conditions (with a TLR7/<NUM> agonist (R848), a reference anti-helminthic drug known to display anti-cancer properties (mebendazole), and antihyperglycemic agent (metformin), on the killing capacity of human immune cells - to promote cell death in tumor cell populations.

The experimental conditions that were performed in the study are summarized in the table below:.

The experimental procedure is described as follows:.

This in vitro study particularly aimed at evaluating the effect of four compounds ; a TLR7/<NUM> agonist (R848), metformin - an antihyperglycemic agent, known to impair cellular metabolism (and can thus suppress oncogenic signaling pathways includ-ing PI3K/Akt and mTOR signaling pathways), mebendazole (anti-helminthic agent), and Ginsenoside Rh2 known to induce ER-stress mediated apopto-sis,each alone and in combination of two and three, for their ability to modulate the human immune cell killing activity towards A549 lung cells.

From this study, the following points can be depicted:.

Among the most common inflammatory cytokines as biomarkers of iRAEs is IL-<NUM> which is also known to be a surrogate of immune response, inflammation, tumor progression and pain. Serum IL-<NUM> is associated with worse prognosis and poor survival in cancer patients. Among the first treatments of iRAEs such severe arthri-tis, myocarditis, uveitis, great vasculitis, severe pneumonia, great vasculitis and myasthenia gravis is Tocilizumab (Anti IL-<NUM> Receptor antibody) which inhibits IL-<NUM> signaling. Targeting IL-<NUM> pathway does not activate tumor progression.

Therefore, tumor cell killing without triggering IL-<NUM> and/or activate IL-<NUM> signaling pathways and other inflammatory cytokines pose as great benefit for patients such as inhibiting cancer cachexia, physical and neuropathic pain and fatigue- thus contributing towards improving quality of life. The combination of Ginsenoside and Mebendazole trigger a non-inflammatory, antigen independent immune-mediated tumor cell killing without the secretion of IL-<NUM> and TNF-alpha. Therefore, Ginseno-side and Mebendazole combination reduces cytokine release commonly associated with cancer cachexia, physical and neuropathic pain, fatigue and poor quality of life.

In co-cultures with activated PBMCs, there was more TNFa released than with in-activated PBMCs, and these levels were not further increased under R848 or mebendazole treatment. On the other hand, metformin and Ginsenoside Rh2 were shown, each alone or when applied in combination together, to completely abolish this release. While this release was strongly inhibited under metformin in combination with mebendazole, the inhibitory effect of metformin seemed like partially reversed by R848.

However, IL6 release increased in co-cultures with inactivated PBMCs and even more with activated PBMCs. In both cases, IL6 levels were shown to be slightly optimized by Atezolizumab.

With regards to compounds treatments, in the absence of anti-CD3, R848 interest-ingly displayed a very huge induction of IL6 release, while the three other com-pounds - applied either alone or in combination between them - rather showed an inhibitory action. Also, interestingly, the R848-induced IL6 release was increasing-ly inhibited by mebendazole, metformin, and mebendazole+metformin, respective-ly.

In co-culture with activated PBMCs, IL6 release was very strong in control untreated conditions but remained, slightly, increased by R848 treatment. Also, the inhibitory effects of metformin, Ginsenoside Rh2, and mebendazole were still evidenced, both when they were applied each alone or in combination between them thereby underlining a synergistic inhibition. However, these inhibitory effects were shown, interestingly, to be reversed in the presence of R848, suggesting that TLR7/<NUM> stimulation in the condition of activated immune cells antagonizes the inhibitory modulatory effect of metformin, Ginsenoside Rh2, and mebendazole.

All these effects were supported, and even completed by the kinetic live cell anal-yses of tumor cell count and apoptosis (<FIG>). Indeed, these data showed that:.

In addition, while mebendazole and metformin combination, and mebendazole and R848 combination seemed to provide an equivalent tumor cell death rate similar to that induced by mebendazole alone, combination of metformin with R848 showed no particular effect when compared to that of R848 alone. The triple combination showed however an optimized effect trend, particularly likely underlied by mebendazole.

Conversely, metformin application was shown to induce a decrease in tumor cell death. Interestingly, this effect disappeared when metformin was co-applied with mebendazole, and even more, metformin did not seem to impact the effect of mebendazole, while it was able to abolish that of R848. More interestingly, the presence of mebendazole along with R848 was shown to completely reverse the inhibitory metformin effect against R848- enhanced tumor cell death.

Contrary to its effects when combined with R848, metformin was shown to opti-mize the effect of Ginsenoside Rh2, whereas, in the presence of mebendazole, this optimization seemed to be abolished. These last effects with regards to metformin activities also suggest an antagonism between mebendazole and metformin.

Claim 1:
A composition for use in a method of treating cancer, the composition comprising an effective amount of at least one saponin agent and an effective amount of at least one anthelmintic agent, wherein the saponin agent is a ginsenoside and the anthelmintic agent is a methyl N-(<NUM>-benzoyl-<NUM>-benzimidazol-<NUM>-yl)carbamate (mebendazole).