阅读说明：本技术 用于治疗脑癌的方法 (Methods for treating brain cancer ) 是由 詹维康 陈咨锜 于 2020-01-03 设计创作，主要内容包括：本发明涉及一种用于治疗脑癌的方法。本发明提供一种用于治疗需要此类治疗的个体的脑癌的方法,其包括向所述个体投与包括有效量的具有至少一个(经取代苯基)-丙烯醛部分的化合物和任选地药学上可接受的载剂或赋形剂的药物组合物,可有效治疗脑癌。(The present invention relates to a method for treating brain cancer. The present invention provides a method for treating brain cancer in an individual in need of such treatment, comprising administering to the individual a pharmaceutical composition comprising an effective amount of a compound having at least one (substituted phenyl) -propenal moiety, and optionally a pharmaceutically acceptable carrier or excipient, effective to treat brain cancer.)

1. A method for treating brain cancer in a subject in need of such treatment, comprising administering to the subject a pharmaceutical composition comprising an effective amount of a compound according to formula VIII, and optionally a pharmaceutically acceptable carrier or excipient;

R₁₈and R₂₈Is a mono or di-substituted group and is independently selected from the group consisting of: methoxy, hydroxy and alkylsulfonyl;

R₃₈selected from the group consisting of:

(CH₂)₃CH₃、and is

R₄₈Selected from the group consisting of: CH (CH)₃H, F and Cl; and is

n₈Is 1 or 2.

2. The method of claim 1, wherein R₁₈And R₂₈Is disubstituted methoxy, R₃₈Is composed ofR₄₈Is H, and n₈Is 1.

3. The method of claim 1, wherein the cancer is a multi-drug resistant cancer.

4. The method of claim 1, wherein the brain cancer is temozolomide-resistant brain cancer.

5. The method of claim 1, wherein the brain cancer is a primary brain cancer.

6. The method of claim 5, wherein the primary brain cancer is glioma, meningioma, pituitary adenoma, vestibular schwannoma, primitive neuroectodermal tumor (medulloblastoma), germ cell tumor, neuroblastoma, or craniopharyngioma.

7. The method of claim 6, wherein the glioma is glioblastoma, glioblastoma multiforme, astrocytoma, microneuroma, or ependymoma.

8. The method of claim 1, wherein the cancer is secondary brain cancer.

9. The method of claim 8, wherein the primary site of the secondary brain cancer is breast cancer, colorectal cancer, kidney cancer, lung cancer, lymphoma, myeloma, pancreatic cancer, liver cancer, prostate cancer, bladder cancer, skin cancer, non-hodgkin's lymphoma, leukemia, uterine cancer, adrenal cancer, stomach cancer, bile duct cancer, bone cancer, ovarian cancer, laryngeal cancer, oral cancer, head and neck cancer, thyroid cancer, soft tissue sarcoma, testicular cancer, vaginal cancer, or melanoma.

Technical Field

The present invention relates to a method of treatment, more precisely, the invention provides a method of treatment of brain cancer with compounds having at least one (substituted phenyl) -propenal moiety and uses thereof.

Background

It is well known that certain natural products can have therapeutic effects, which have led to their use in many cultures for the treatment and prevention of human diseases (e.g. chinese herbs and many other folk medicines). The effectiveness of such treatments has led the pharmaceutical industry to seek and isolate active compounds from these natural products and to develop active ingredients as therapeutic or prophylactic agents for the treatment and prevention of various diseases or medical conditions. Thus, many commonly used drugs have been developed or produced from natural products. However, compounds isolated from natural products are known to exert certain physiological functions in their natural hosts; and their therapeutic effect against human diseases is not readily apparent. Historically, the therapeutic treatment was only deduced by cumulative experience or "trial and error" in humans. Furthermore, because the compounds are not originally produced for human use, the compounds in their native form are often not structurally and functionally optimal for the treatment of human diseases. However, as of today, modern chemical technology, including analytical and synthetic chemistry methods, as well as advances in pharmaceutical biology have made possible the dissection of chemical structures and the localization of "pharmacophores" (core structures critical for therapeutic activity) within a compound (e.g., one isolated from a natural product); furthermore, these novel techniques allow the synthesis of novel compounds with optimal or even better therapeutic efficacy based on the structure of the pharmacophore.

The compound curcumin (present as the major pigment in turmeric plants) and many of its analogs have been reported to possess a number of biological activities in vitro, such as antioxidant, anti-inflammatory, anti-tumor and anti-angiogenic activities; however, none of curcumin or its analogs have been developed as therapeutic agents for the treatment of human diseases. This suggests that curcumin in its native form may not be the optimal molecule for development into a therapeutic drug. Therefore, there is a need to develop curcumin analogs suitable for clinical use.

Glioblastoma multiforme (GBM) is a lethal disease, and patient survival averages 14 months. Most patients do not survive for more than two years (Argine holly S (agnihotris S), Braille KE (BurrellKE), Wulff A (wolf A), et al, "glioblastomas, brief review of History, molecular genetics, animal models and novel treatment strategies (Glioblastoma, a brif review of history, molecular genetics, animal models and novel treatment strategies.) (Arch Immunol Ther Exp (Warsz.). 2013; 61(1): 25-41; Wilson TA (Wilson TA), Karah Nissian MA (Karajannis MA.), Harr multiform advanced glioma: advanced glioma and future (neuron of surgery of neurology, 20145).

Median survival from surgical resection alone was approximately 6 months (Wilson TA, Calnazenis MA, hate DH. glioblastoma multiforme: Current advanced technology and future therapies: International surgical neurology 2014; 5: 64). It has further been demonstrated that treatment with radiation and Temozolomide (TMZ), followed by the adjuvant temozolomide, simultaneously increased median Overall Survival (OS) from 12.1 months to 14.6 months compared to patients receiving radiation alone (argoni hodrid S, brel KE, wulff a et al, "glioblastoma, short reviews of history, molecular genetics, animal models and novel treatment strategies" [ archives of immunology and experimental therapy (huasha) ] 2013; 61(1): 25-41). Despite intensive initial treatment, tumor recurrence is almost inevitable and 5-year-old patients with GBM remain below 9% (argoni Hotel S, Braille KE, Wulff A et al, "glioblastoma, history, molecular genetics, animal models and short reviews of novel treatment strategies." archives immunology and experimental therapy (Wash.) 2013; 61(1): 25-41; Ostrom QT, Kittleman H (Gittleman H), J (xu J) et al, "CBTRUS statistics report that Primary Brain and Other Central Nervous System Tumors (CBUS statistical report: Primary Brain in and Others Central Nervous System Tumors) Diagnosed in the United States during 2009 and 2013;" neural proliferation in 2013., "New 2013": 20184. Others 19818). The effectiveness of current conventional therapies remains poor, creating an unmet medical need for treatment of GBM.

Disclosure of Invention

The present invention provides a method for treating brain cancer in a subject in need of such treatment, comprising administering to the subject a pharmaceutical composition comprising an effective amount of a compound according to formula VIII;

R₁₈and R₂₈Is a mono or di-substituted group and is independently selected from the group consisting of: methoxy, hydroxy and alkylsulfonyl;

R₃₈selected from the group consisting of:

(CH₂)₃CH₃、and is

R₄₈Selected from the group consisting of: CH (CH)₃H, F and Cl; and is

n₈Is 1 or 2.

The present invention is described in detail in the following sections. Other features, objects, and advantages of the invention will be apparent from the description and from the claims.

Drawings

Fig. 1A to 1B show that ASC-JM17(JM17) inhibits proliferation of glioblastoma cells with or without Temozolomide (TMZ) resistance. FIG. 1A: after 48 hours of treatment, TMZ sensitive a172 and Pt #3, and TMZ resistant a172-R cells were collected for MTT assay. Differences between the 2 groups were analyzed by Student's t test. FIG. 1B: phase images of cells treated with JM17 or vehicle (DMSO) as indicated. The cells were photographed. Right panel: after 48 hours of treatment, TMZ sensitive U87MG (top) and TMZ resistant U87MG-R (bottom) cells were collected for MTT analysis (. P <0.05,. P <0.01,. P < 0.001).

Figures 2A to 2B show that ASC-JM17(JM17) induces apoptosis in glioblastoma cells as evidenced by the increased activity of caspase 3/7, 8 and 9. Use of3/7, 8, and 9 assay kits (Company) and by photometer (Company) detected a signal indicative of caspase. Determination of caspase 3/7, caspase 8 and caspase 9 activity (. about.P.) in supernatants of cultured glioblastoma cells treated with JM17 for 48 hours<0.05，**P<0.01)。

Figures 3A to 3D show that ASC-JM17(JM17) increases ROS production and induces oxidative stress in GBM cells. FIG. 3A: u87MG cells were treated for 48 hours prior to harvest and ROS production was measured by flow cytometry using dihydrorhodamine 123 (DHR). Histograms from representative experiments showed a shift in fluorescence to the right in JM 17-treated cells compared to untreated controls. The results were quantified as mean fluorescence and presented in the right panel. In addition, with increasing concentrations of JM17 and H₂O₂U87MG and primary human GBM cells Pt #3 (fig. 3B) were treated horizontally, and the GSH/GSSG ratio (fig. 3C) and GSHR activity (fig. 3D) were measured. P and # P indicate statistical significance between the untreated control group and the U87MG and Pt #3 treated groups (, P, # P), respectively<0.05，**P<0.01)。

FIGS. 4A to 4C show the therapeutic effect of ASC-JM17(JM17) on growth of glioblastoma in vivo FIG. 4A luciferase-expressing U87MG cells (2 × 10)⁵) Intracranial transplantation into the brain of nude mice. After 10 days, atLuciferase activity indicative of tumor size was monitored by the IVIS200 system at day 10, day 13, day 20, and day 27. Mice were administered either vehicle or JM17 intravenously at doses of 20mg/kg, 40mg/kg and 80mg/kg three times a week starting on day 10. Left side: timeline for IVIS200 evaluation and drug injection. FIG. 4B: statistical analysis of luciferase activity by two-way ANOVA analysis (. about.p)<0.0001). fig. 4C comparison of survival time (. about.p.) using log Rank Test (L og-Rank Test)<0.0001). JM17 dosing was terminated on day 63.

Figure 5 shows a schematic presentation of the experimental design and performance in a glioblastoma multiforme (GBM) animal model. Animal survival was assessed from the first day of treatment until death. Body weight was measured twice a week.

FIG. 6 shows the effect of ASC-JM17(JM17) treatment on animal survival. The TMZ-resistant GBM was inoculated into orthotopic mice randomized into groups and treated with TMZ or TMZ plus JM 17. Survival (, p <0.01) was plotted using a Kaplan-Meier curve (Kaplan-Meier curve).

FIG. 7 shows that ASC-JM17(JM17) prevented weight loss in GBM vaccinated mice. Body weight of TMZ-resistant GBM inoculated with TMZ or TMZ plus JM17 in situ mice was measured twice a week. Body weight statistics on day 21 were analyzed using the schradert test. # p <0.01TMZ + vehicle control TMZ + JM17(5 mg/kg); p <0.01TMZ + vehicle control TMZ + JM17(20 mg/kg).

Detailed Description

The present invention may be understood more readily by reference to the following detailed description of various embodiments of the invention, the examples and the chemical diagrams and tables having associated descriptions. It is to be understood that, unless otherwise specifically indicated by the claims, the invention is not limited to a particular method of manufacture, carrier, or formulation, or to a particular mode of formulating the compounds of the invention into products or compositions intended for topical, oral, or parenteral administration, as such may, of course, vary, as is well understood by those of ordinary skill in the relevant art. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

The present invention provides a method for treating brain cancer in a subject in need of such treatment, comprising administering to the subject a pharmaceutical composition comprising an effective amount of a compound having a (substituted phenyl) -propenal moiety, preferably according to formula VIII, and optionally a pharmaceutically acceptable carrier or excipient;

R₁₈and R₂₈Is a mono or di-substituted group and is independently selected from the group consisting of: methoxy, hydroxy and alkylsulfonyl;

R₃₈selected from the group consisting of:

(CH₂)₃CH₃、and is

R₄₈Selected from the group consisting of: CH (CH)₃H, F and Cl; and is

n₈Is 1 or 2.

As used herein, the term "(substituted phenyl) -acrolein moiety" refers to a composition comprising a phenyl group having an acrolein moiety (when m equals 1) and an alkoxy or hydroxyl moiety, or an alkyl or substituted alkyl moiety attached thereto. The substitution may be positioned meta or para or ortho with respect to the acrolein moiety as used herein, and refers to the general formulaWherein q may be any number of 1, 2, 3 or 4; and m can be any number of 1, 2, 3,4, or more.

As used herein, the term "alkyl" refers to a straight or branched hydrocarbon chain group consisting of only carbon and hydrogen atoms, containing no unsaturated groups, having one to ten carbon atoms, and attached to the rest of the molecule by single bonds, such as methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1-dimethylethyl (tert-butyl), and the like.

As used herein, the term "alkenyl" refers to a straight or branched hydrocarbon chain group consisting solely of carbon and hydrogen atoms, containing at least one double bond, having two to ten carbon atoms, and attached to the remainder of the molecule by single or double bonds, such as vinyl, prop-1-enyl, pent-1, 4-dienyl, and the like.

The term "alkenylene" as used herein refers to a compound containing a carbon-carbon double bond and represented by the formula C_pH_2p-2Straight or branched hydrocarbon chains are represented wherein the hydrogen may be replaced by additional carbon-carbon double bonds or monovalent substituents (e.g., ethenylene, prop-1-enylene, etc.).

The term "alkoxy" as used herein refers to a group having the formula-OR, wherein R is alkyl, haloalkyl, OR cycloalkyl. "optionally substituted alkoxy" refers to a group having the formula-OR ', wherein R' is optionally substituted alkyl as described herein.

As used herein, the term "alkynyl" refers to a straight or branched hydrocarbon chain group consisting solely of carbon and hydrogen atoms, containing at least one triple bond, having two to ten carbon atoms, and attached to the remainder of the molecule by a single or triple bond, such as, for example, ethynyl, prop-1-ynyl, but-1-ynyl, pent-3-ynyl, and the like.

As used herein, the term "aryl" refers to a group of a carbocyclic ring system in which at least one of the rings is aromatic. The aryl group may be fully aromatic or may contain a combination of aromatic and non-aromatic rings. A "biaryl system" is a compound comprising at least two aryl groups.

As used herein, the term "cycloalkyl" refers to a stable monovalent monocyclic or bicyclic hydrocarbon group consisting only of carbon and hydrogen atoms, having three to ten carbon atoms, and being saturated and attached to the rest of the molecule by single bonds, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

As used herein, the term "diketone bridge" or "keto-enol bridge" refers to a linear or branched hydrocarbon chain containing two ketones or an enol positioned in close proximity to a ketone, respectively. A "diketone bridge" or "keto-enol bridge" is located between at least two aryl moieties.

As used herein, the term "hydroxyalkyl" refers to a straight or branched hydroxy-substituted hydrocarbon chain radical having from one to ten carbon atoms, e.g., -CH₂OH、-(CH₂)₂OH and the like.

In a preferred embodiment of the invention, the compounds comprise a 4, 4-disubstituted 1, 7-bis- (3, 4-dimethoxyphenyl) -hepta-1, 6-diene-3, 5-dione and a 6, 6-disubstituted 1, 11-bis (substituted phenyl) -undec-1, 3,8, 10-tetraene-5, 7-dione framework as shown in table 1.

Table 1:

in another preferred embodiment of the invention, the compound is of formula VIII, R₁₈And R₂₈Is disubstituted methoxy, R₃₈Is composed ofR₄₈Is H, and n₈Is 1 and is called ASC-JM 17.

The present invention also provides a composition comprising a compound having a (substituted phenyl) -propenal moiety. The composition according to the invention is preferably a pharmaceutical, food or cosmetic composition.

Preferably, the pharmaceutical composition comprises a compound having a (substituted phenyl) -propenal moiety and optionally a pharmaceutically acceptable carrier or excipient.

Preferably, the pharmaceutical composition comprises an effective amount of the compound.

Typically, ranges are expressed herein as "about" one particular value, and/or to "about" another particular value. When such a range is expressed, an embodiment includes one particular value and/or a range to another particular value. Similarly, when values are expressed as approximations, by use of the word "about," it will be understood that the particular value forms another embodiment. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint.

"optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, the phrase "optionally including an agent" means that the agent may or may not be present.

It must be noted that, as used in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, unless the context requires otherwise, singular terms shall include the plural and plural terms shall include the singular.

As used herein, the term "individual" means any animal, preferably a mammal, and more preferably a human. Examples of subjects include humans, non-human primates, rodents, guinea pigs, rabbits, sheep, pigs, goats, cows, horses, dogs, and cats.

The term "effective amount" of an active ingredient as provided herein means a sufficient amount of the ingredient to be adjusted to provide the desired function. As will be noted below, the exact amount required will vary from individual to individual depending on the disease state, physical condition, age, sex, species and weight of the individual, the particular characteristics and formulation of the composition, and the like. The dosing regimen may be adjusted to induce an optimal therapeutic response. For example, several divided doses may be administered daily, or the dose may be proportionally reduced as indicated by the state of urgency of the treatment situation. Therefore, it is not possible to specify an exact "effective amount". However, an appropriate effective amount can be determined by one of ordinary skill in the art using only routine experimentation.

As used herein, the term "treating" or "treatment" means reversing, alleviating, inhibiting the progression of, or improving: the term applies to a disorder, disease, or condition, or one or more symptoms of the disorder, disease, or condition.

As used herein, the term "carrier" or "excipient" refers to any substance that is not a therapeutic agent by itself, that acts as a carrier and/or diluent and/or adjuvant, or vehicle, for delivering a therapeutic agent to an individual or adding to a formulation to improve its handling or storage characteristics, or to permit or facilitate the formation of dosage units of a composition into discrete articles suitable for oral administration, such as capsules or tablets. Suitable carriers or excipients are well known to those of ordinary skill in the art of making pharmaceutical formulations or food products. The carrier or excipient may include, by way of illustration and not limitation, buffers, diluents, disintegrants, binders, adhesion agents, wetting agents, polymers, lubricants, glidants, substances added to mask or counteract an unpleasant taste or odor, flavoring agents, dyes, fragrances, and substances added to improve the appearance of the composition. Acceptable carriers or excipients include citrate buffers, phosphate buffers, acetate buffers, bicarbonate buffers, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acid, magnesium carbonate, talc, gelatin, acacia, sodium alginate, pectin, dextrin, mannitol, sorbitol, lactose, sucrose, starch, gelatin, cellulosic materials (e.g., cellulose esters and cellulose alkyl esters of alkanoic acids), low melting wax cocoa butter, amino acids, urea, alcohols, ascorbic acid, phospholipids, proteins (e.g., serum albumin), Ethylene Diamine Tetraacetic Acid (EDTA), dimethyl sulfoxide (DMSO), sodium chloride or other salts, liposomes, mannitol, sorbitol, glycerin or powders, polymers (e.g., polyvinyl-pyrrolidone, polyvinyl alcohol, and polyethylene glycol), and other pharmaceutically acceptable materials. The carrier should not destroy the pharmacological activity of the therapeutic agent and should be non-toxic when administered at a dose sufficient to deliver a therapeutic amount of the agent.

The pharmaceutical compositions according to the present invention are preferably administered systemically by any method known in the art, including, but not limited to, intramuscular, intradermal, intravenous, subcutaneous, intraperitoneal, intranasal, oral, mucosal or external routes. The appropriate route, formulation and dosing schedule can be determined by one of skill in the art. In the present invention, the pharmaceutical composition may be formulated in various ways according to the respective routes of administration, such as liquid solutions, suspensions, emulsions, syrups, tablets, pills, capsules, sustained-release formulations, powders, granules, ampoules, injections, infusions, kits, ointments, emulsions, liniments, creams or combinations thereof. If necessary, it can be sterilized or mixed with any pharmaceutically acceptable carrier or excipient, many of which are known to those of ordinary skill in the art.

As used herein, external routes are also referred to as topical administration, including, but not limited to, administration by insufflation and inhalation. Examples of various types of formulations for topical administration include ointments, creams, gels, foams, formulations for delivery by transdermal patches, powders, sprays, aerosols, capsules or cartridges for inhalers or insufflators or drops (e.g., eye drops or nasal drops), solutions/suspensions for nebulization, suppositories, pessaries, retention enemas, and chewable or suckable tablets or granules or liposomes or microencapsulated formulations.

Ointments, creams and gels may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents and/or solvents. The base may thus for example comprise water and/or an oil, such as liquid paraffin or a vegetable oil, such as peanut oil or castor oil, or a solvent, such as polyethylene glycol. Thickeners and gelling agents which may be used depending on the nature of the base include soft paraffin, aluminium stearate, cetostearyl alcohol, polyethylene glycol, lanolin, beeswax, carboxypolymethylene and cellulose derivatives and/or glyceryl monostearate and/or nonionic emulsifiers.

Emulsions may be formulated with an aqueous or oily base and will generally also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents or thickening agents.

Powders for external application may be formed with the aid of any suitable powder base, such as talc, lactose or starch. Drops may be formulated with an aqueous or non-aqueous base also including one or more dispersing agents, solubilizing agents, suspending agents or preservatives.

The spray compositions may be formulated, for example, as aqueous solutions or suspensions, or as aerosols delivered from pressurized packs (e.g., metered dose inhalers), using a suitable liquefied propellant. Aerosol compositions suitable for inhalation may be suspensions or solutions. The aerosol composition may optionally contain additional formulation excipients well known in the art, such as surfactants, for example oleic acid or lecithin, and co-solvents, for example ethanol.

The topical formulation may be administered to the affected area by one or more applications per day; an occlusive dressing may be advantageously used on the skin area. Continuous or long term delivery can be achieved by a bonded reservoir system.

The cosmetic composition according to the invention may be an aqueous phase formulation consisting essentially of water; it may also include a mixture of water and a water-miscible (miscibility in water greater than 50 wt% at 25 ℃) solvent, for example, a lower monoalcohol containing from 1 to 5 carbon atoms, such as ethanol or isopropanol; diols having 2 to 8 carbon atoms, such as propylene glycol, ethylene glycol, 1, 3-butanediol or dipropylene glycol, C3-C4 ketones and C2-C4 aldehydes; and glycerol. The aqueous formulation is preferably in the form of an aqueous gel or hydrogel formulation. The hydrogel formulation includes a thickener to thicken the liquid solution. Examples of thickeners include, but are not limited to, carbomers, cellulosic based materials, gums, algins, agar, pectins, carrageenans, gelatin, mineral or modified mineral thickeners, polyethylene glycols and polyols, polyacrylamides, and other polymeric thickeners. Thickeners are preferably used which provide stability and optimal flow characteristics of the composition.

The cosmetic composition according to the invention may be in the form of an emulsion or cream formulation. It may contain an emulsifying surfactant. These surfactants may be selected from anionic and nonionic surfactants. With regard to the definition of the properties and function (emulsification) of surfactants, reference may be made to the Encyclopedia of chemical Technology, Kock-Othmer, 22, 333-432, 3 rd edition, 1979, Weili (Wiley), in particular, said reference at 347-377 relates to anionic and nonionic surfactants.

Preferably the surfactants used in the cosmetic compositions according to the invention are selected from: nonionic surfactant: fatty acids, fatty alcohols, polyethoxylated or polyglycerolated fatty alcohols (such as polyethoxylated stearyl alcohol or cetylstearyl alcohol), fatty acid esters of sucrose, alkyl glucose esters (specifically, polyoxyethylated fatty esters of C1-C6 alkyl glucose), and mixtures thereof; anionic surfactant: a C16-C30 fatty acid neutralized with an amine, aqueous ammonia or a basic salt, and mixtures thereof. Preferably surfactants are used which make it possible to obtain oil-in-water or wax-in-water emulsions.

The cosmetic composition according to the present invention may further comprise an effective amount of a physiologically acceptable antioxidant selected from the group consisting of: butylated p-cresol, butylated hydroquinone monomethyl ether and tocopherol.

The cosmetic composition according to the present invention may further include natural or modified amino acids, natural or modified sterol compounds, natural or modified collagen, silk protein or soybean protein.

The cosmetic composition according to the invention is preferably formulated for topical application to keratin materials such as the skin, hair, eyelashes or nails. It may be in any presentation form commonly used for this type of application, in particular in the form of an aqueous or oily solution, an oil-in-water or water-in-oil emulsion, a silicone emulsion, a microemulsion or nanoemulsion, an aqueous or oily gel or a liquid, paste-like or solid anhydrous product.

The cosmetic composition according to the invention may be nearly fluid and may have the appearance of a white or colored cream, ointment, milk, lotion, serum, paste, mousse or gel. It may optionally be topically applied to the skin in the form of an aerosol, patch or powder. It may also be in solid form, for example in the form of a stick. It can be used as a skin care product and/or as a cosmetic product for the skin. Alternatively, it can be formulated into shampoo or hair conditioner.

The cosmetic compositions according to the invention may also contain, in a known manner, additives and adjuvants commonly found in cosmetics, such as hydrophilic or lipophilic gelling agents, preservatives, antioxidants, solvents, fragrances, fillers, pigments, odour absorbers and dyes.

The compound may be added to a conventional food composition (i.e., an edible food or beverage or precursor thereof) during the manufacture of the food composition. Almost all food compositions can be supplemented with the compounds of the present invention. Food compositions that can be supplemented with the compounds of the present invention include, but are not limited to, confections, baked goods, ice creams, dairy products, sweet and flavored snacks, snack bars, meal replacement products, snack foods, soups, pasta, noodles, canned foods, frozen foods, dried foods, chilled foods, oils and fats, baby foods, or soft foods coated on bread, or mixtures thereof.

While not wishing to be bound by theory, applicants believe that the method according to the present invention is to treat brain cancer by inducing Reactive Oxygen Species (ROS) in cancer cells, or inducing lipid oxidation on the membranes of cell membranes and internal organelles in cancer cells.

Reduction-oxidation (redox) state is used to describe GSH/GSSG, NAD in biological systems such as cells or organs⁺NADH and NADP⁺The balance of/NADPH. The redox state is reflected in the equilibrium of several groups of metabolites whose interconversion depends on these ratios. Abnormal redox states can develop in a variety of deleterious situations. Free radical reactions are redox reactions that occur as part of the homeostasis and kill microorganisms, with electrons being separated from molecules and then nearly soThe connection is immediately reconnected. Reactive Oxygen Species (ROS) are part of redox molecules and can become harmful to humans if they are not re-attached to redox molecules or antioxidants. Unsatisfied free radicals may stimulate mutations in the cells they encounter and thus be responsible for cancer and other diseases (R Cohen (R Kohen), Anima (A Nyska).

Compounds having a (substituted phenyl) -propenal moiety modulate the homeostasis of redox conditions in various types of cells, tissues and organs. In tumors, compounds with (substituted phenyl) -propenal moieties induce lipid oxidation on cell membranes and membranes of internal organelles and produce high oxidative stress levels causing cell damage and cell death. In turn, the ROS lipid produced by compounds with (substituted phenyl) -acrolein moieties enables a variety of cellular and molecular reactions to respond to cellular damage, such as increased expression of chaperones, activation of the ubiquitin-proteasome system, alterations in mitochondrial biosynthesis, Unfolded Protein Response (UPR), disruption of protein homeostasis, autophagy, and apoptosis. These multiple cellular responses ultimately lead to cancer cell death through apoptosis and autophagy.

While not wishing to be bound by theory, applicants believe that the method according to the invention is to treat brain cancer by increasing chaperonin expression.

While not wishing to be bound by theory, applicants believe that the method according to the present invention is to treat brain cancer by activating the ubiquitin-proteasome system.

While not wishing to be bound by theory, applicants believe that the method according to the invention is to treat brain cancer by altering mitochondrial biosynthesis.

While not wishing to be bound by theory, applicants believe that the method according to the present invention is to treat brain cancer by activating the Unfolded Protein Response (UPR).

While not wishing to be bound by theory, applicants believe that the method according to the invention is to treat brain cancer by disrupting protein homeostasis.

While not wishing to be bound by theory, applicants believe that the method according to the invention is to treat brain cancer by activating autophagy.

While not wishing to be bound by theory, applicants believe that the method according to the present invention is to treat brain cancer by activating apoptosis.

In a preferred embodiment of the invention, the brain cancer is a multi-drug resistant cancer; preferably, the brain cancer is temozolomide-resistant brain cancer.

Preferably, the brain cancer is a primary brain cancer. The primary brain cancer is preferably glioma, meningioma, pituitary adenoma, vestibular schwannoma, primitive neuroectodermal tumor (medulloblastoma), germ cell tumor, neuroblastoma, or craniopharyngioma. Preferably, the glioma is a glioblastoma, glioblastoma multiforme, astrocytoma, micronuture neuroma or ependymoma.

Using various cell models of GMB, applicants have obtained a large body of experimental evidence that ASC-JM17 exhibits toxicity in glioblastoma cells by inducing oxidative stress and by activating extrinsic and intrinsic apoptotic pathways. Furthermore, in a validated animal model of GBM, ASC-JM17 exhibits the ability to alleviate clinically significant morbidity (weight loss) and, most importantly, is able to improve the overall survival of the experimental animals. The anti-cancer effects of ASC-JM17 were demonstrated in models of TMZ sensitive and TMZ resistant GBM, making these findings particularly relevant to unmet medical needs of GBM patients.

Taken together, these data strongly support that ASC-JM17 may provide benefits to GMB patients.

Preferably, the brain cancer is a secondary brain cancer. In a preferred embodiment of the invention, the primary site of secondary brain cancer is breast cancer, colorectal cancer, kidney cancer, lung cancer, lymphoma, myeloma, pancreatic cancer, liver cancer, prostate cancer, bladder cancer, skin cancer, non-Hodgkin lymphoma, leukemia, uterine cancer, adrenal cancer, stomach cancer, bile duct cancer, bone cancer, ovarian cancer, laryngeal cancer, oral cancer, head and neck cancer, thyroid cancer, soft tissue sarcoma, testicular cancer, vaginal cancer, or melanoma.

The following examples are provided to assist those skilled in the art in practicing the invention.

Examples of the invention

Example 1: efficacy of ASC-JM17(JM17) in an in vitro model of glioblastoma multiforme (GBM)

JM17 exhibits cytotoxic effects selectively against TMZ resistant glioblastoma

The effect of JM17 on the proliferation of GBM cells was studied in several cell lines independently derived from GBM cancer. First, well characterized and commercially available a172 and U87MG cells were purchased from ATCC: (a)CE LL L INES BY GENEMUTATION.2019. secondly, primary glioblastoma cells Pt #3 were derived from GBM patients (often KY (Chang KY), many TI (Hsu TI), many CC (Hsu CC), et al, specific protein 1-regulated superoxide dismutase 2, following published procedures, which enhanced temozolomide resistance in glioblastoma independently of O (6) -methylguanine-DNA methyltransferase (specific protein 1-modulated superoxide dismutase 2 enzyme) mediated Redox biology (Redox Biol. 2017; human being transgenic for O (6) -methylguanine-methyltransferase) mediated DNA, world is found in (6) -methyl guanamine-methylated mutant, Genencor. Redox Biol. 20113: 664; gene expression of Chnem amino-methylated DNA transferase), human being genetically modified DNA L, protected BY CYP 17-mediated DNA, P17-mediated BY CYP17A, 9-mediated resistance in glioblastoma cells Pt #3, BY following published procedures, which confers protection on human being genetically modified superoxide dismutase 2, P17A, 2 mediated BY CYP 17-mediated DNA (genetically modified coenzyme A3) mediated BY CYP17A, 9, 2-mediated BY CYP 11, P17-mediated DNA protection in human being mediated BY CYP 2, P2-mediated BY CYP 11A, 3, 2-mediated BY genetically modified human being able DNA, which confers resistance to human being derived from genetically modified human being able DNA, e-mediated BY CYP (genetically modified human being able DNA, e-mediated BY CYP 3, e.A, e.3, e.AIn addition, Temozolomide (TMZ) resistant clones producing U87MG and A172 according to published protocols (Ky, permit CC et al, "protein 1-regulated superoxide dismutase 2enhances temozolomide resistance in glioblastoma) independent of O (6) -methylguanine-DNA methyltransferase", Redox Biotechnology 2017; 13: 664; Zhuang JY, RoW L, Cocy et al human neuroglioma, Regulation on CYP17A1 mediated by DNA demethylation via Sp1 confers temozolomide resistance on CYP17A1 mediated by Protection mediated by the SpEA mediated protection ", Teozolomide tumor formation", Timezolomide resistance in ZU 11, Pro 7, Pro 2, Metro-D-K12, and the like human T17A 1 mediated by Sp-D-M2 mediated protein transferase, and the presence of growth of protein 1-mediated protein transferase in DMSO 1, Pro 2, Metro-D1, Metro-D-E, and the presence of MTZ resistant clones in the MTZ resistant clones (Ky-K-D-K2, and the presence of the growth of the cells is measured by a monoclonal antibody in a culture medium, the following a culture medium of a culture medium, the culture medium of.

As shown in fig. 1A and 1B, JM17 significantly reduced proliferation of TMZ-sensitive cells a172 and Pt #3 and the TMZ-resistant glioblastoma cell line, a 172-R. Furthermore, proliferation of TMZ sensitive U87MG and TMZ resistant U87MG-R was inhibited by JM17 in a time and dose dependent manner (fig. 1B).

Notably, JM17 had no effect on the survival of normal mouse astrocytes at concentrations up to 10 μ M (data not shown), indicating that the drug was less toxic to non-cancerous cells.

To further elucidate the mechanism of action of JM17 on glioblastoma cells and to assess whether JM17 induced apoptosis, the activity of caspases 3/7, 8 and 9 was measured in the supernatant of cells treated with the drug. JM17 was found to significantly increase the activity of caspase 3/7, 8 and 9 in U87MG and Pt #3 cells at 2 μ M (fig. 2). These data strongly support the concept that JM17 exhibits toxicity in glioblastoma cells by activating both extrinsic and intrinsic apoptotic pathways.

JM17 induces oxidative stress in glioblastoma cells by inhibiting GSHR activity

A cellular Redox imbalance has been found in GBM, indicating that drug intervention to improve cellular Redox homeostasis may provide a positive therapeutic impact (Gorrini C, Harris IS (Harris IS), Mark TW (Mak TW), Modulation of oxidative stress as an anti-cancer strategy (Modulation of oxidative stress as an anti-cancer strategy), Nature review drug discovery 2013, 12 (931) 947, Sarah-Lambda (Salazarr-Ramix A), Lam-Ottaka D (Ramirez-Ortega D), Pererkraz V (Perez de Lacruz V), etc., the Role of the leading edge of Redox state in human Glioblastoma (Role of Redox of Glycodesis of Glycoplast) 42, 2016 (2016). Because increased levels of ROS induce apoptosis, several compounds that increase ROS production have been considered therapeutic agents for GBM (saracher-lamivu a, lamires-ottag D, perzid larkutz V et al, role of redox status in the development of glioblastoma., [ immunological frontier ] 2016; 7: 156).

As shown in fig. 3A to 3D, JM17 significantly increased ROS production in U87MG cells at 2 μ M. In addition, JM17 significantly increased H₂O₂Levels coincident with a decrease in GSH/GSSG ratio (fig. 3B to 3C), indicating JM17 is a potent inducer of oxidative stress in glioblastoma. Furthermore, the glutathione reductase (GSHR) activity responsible for maintaining reduced GSH levels was significantly reduced by JM17 in a dose-dependent manner (fig. 3D). Taken together, these data support the hypothesis that the glioblastoma inhibitory effect of JM17 is mediated by ROS accumulation in cancer cells.

Example 2: efficacy of ASC-JM17(JM17) in glioblastoma multiforme (GBM) animal models

JM17 inhibits growth of glioblastoma in an orthotopic mouse model

To further investigate the in vivo tumor-inhibiting properties of JM17, a GBM mouse model with intracranial-transplanted luciferase-expressing U87MG cells was used.

The experiment was performed as follows. NOD-SCID male mice (8 weeks old) were purchased fromTaiwan limited (taibei taiwan) for intracranial transplantation, luciferase-expressing U87MG cells (2 × 10)⁵) Single injector using stereotactic guidance and microprocessor (Harvard)Holliston, MA, USA was injected into the cortex at a depth of 3 mm. JM17 was administered intravenously three times a week 10 days after transplantation. To prepare formulations for intravenous injection, stock solutions of JM17 in DMSO (50mg/ml) were diluted in PBS with Tween 80 (TM) (Company). Control mice were treated with vehicle (DMSO/PBS/Tween). On day 10 post-transplantation, mice were randomized into four treatment groups (five mice per group) and treated intravenously with vehicle or JM17 three times per week at doses of 20mg/kg, 40mg/kg and 80 mg/kg. Treatment was stopped on day 63. Monitoring luciferase activity by the IVIS200 system (Company, alamidoda, CA, USA) as a measure of tumor size.

The results of this experiment are presented in fig. 4A to 4C. As is evident from fig. 4A, the luciferase activity of U87MG cells was readily detectable at day 10, indicating that the tumor was established at the time of initial treatment. As expected, tumors grew rapidly in the control group receiving vehicle (DMSO). Growth of transplanted U87MG cells was significantly inhibited in JM 17-injected mice (fig. 4A to 4B). Importantly, this inhibition was concentration dependent (fig. 4A).

In addition, the overall survival of mice transplanted with luciferase-expressing U87MG cells was affected by JM17 treatment. All animals from the control group did not survive after day 34 (these mice died from day 27 to day 34). Survival was significantly extended by dosing with 20, 40, and 80mg/kg JM17 to days 34 to 41, 38 to 66, and 44 to 76, respectively (fig. 4C).

These data provide evidence that supports the hypothesis that JM17 can inhibit tumor growth and increase overall survival in GBM patients.

JM17 inhibits growth of TMZ-resistant glioblastoma in an orthotopic mouse model

JM17 has been found to inhibit proliferation of TMZ resistant cells U87MG-R in culture, tumor inhibition by JM17 was further evaluated in an intracranial brain tumor mouse model developed by Others (specific protein 1-regulated superoxide dismutase 2, often KY, permit TI, permit CC, et al, enhances temozolomide resistance in glioblastoma independent of O (6) -methylguanine-DNA methyltransferase, Redox biology 2017; 13: 655) 664. briefly, cranial burr holes were first made in the right frontal lobe brain region, then needles were inserted to a depth of 3mm using stereo static guidance, and 5 × 10 ultrafine was injected⁵TMZ-resistant cells.

Twenty-eight week old nude mice received a U87MG-R transplant. Five days later, the animals were randomized into four treatment groups (7 animals per group) which received TMZ (15mg/kg) by oral gavage three times per week (day 1, day 3, day 5 of the week) and injected intravenously with JM17 as follows: control (untreated), TMZ plus vehicle, TMZ plus JM17(5mg/kg) and TMZ plus JM17(20mg/kg) (FIG. 5).

Median survival for the control (untreated) group was 21 days (fig. 6). As expected, TMZ alone (TMZ plus vehicle) did not affect the survival of animals bearing TMZ-resistant tumors. Median survival for the TMZ vehicle group was 20 days. Median survival of mice was increased to 24 days (at 5mg/kg) and to 28 days (at 20mg/kg) by JM17 treatment. Statistical analysis by log rank testing showed that 20 to 28 day survival prolongation was statistically significant (p < 0.01).

Assessment of body weight is a validated method for monitoring the disease state in experimental mouse cancer studies as a clinically relevant endpoint (passter ev (paster ev), william ka (villines ka), Hickman D L (Hickman D L) & end-point of mouse abdominal tumor model optimization of current standards (objectives for mouse abdominal tumor models: redefinition of current criticism) & compare medicine (Comp Med) 2009, (59): 234-.

While the present invention has been described in conjunction with the specific embodiments set forth above, many alternatives, modifications, and variations thereof will be apparent to those of ordinary skill in the art. All such alternatives, modifications and variations are considered to be within the scope of the present invention.