WO2005118521A1

WO2005118521A1 - Monomethylphytosphingosine and the composition for anti-cancer containing the same

Info

Publication number: WO2005118521A1
Application number: PCT/KR2005/001436
Authority: WO
Inventors: Dae-Seog Lim; Jinwook Kim; Sungjin Park; You-A Hwang; Changseo Park; Ho-Jae Lee
Original assignee: Doosan Corporation
Priority date: 2004-06-01
Filing date: 2005-05-17
Publication date: 2005-12-15
Also published as: KR20050114477A; KR100705054B1

Abstract

Disclosed are a monomethylphytosphingosine (MMPS) or a pharmaceutically acceptable salt thereof and a composition containing the same. The compound can highly inhibit an activity of sphingosine kinase and thus interrupt many mechanisms caused by the sphingosine kinase. In particular, the invention prevents ceramide and sphingosine from being phosphorylated due to sphingosine kinase to maintain concentrations of ceramide and sphingosine to be high, thereby inducing apoptosis of a cancer cell and thus treating or preventing a cancer or a cancer-related disease. In addition, since the invention inhibits a cell proliferation-promoting activity of sphingosine kinase and thus can treat or prevent a hyper-proliferative disease such as cancer or psoriasis.

Description

Description MONOMETHYLPHYTOSPHINGOSINE AND THE COMPOSITION FOR ANTI-CANCER CONTAINING THE SAME Technical Field

[1] The present invention relates to a derivative of sphingoiipid having an anti-cancer activity and a composition containing the same, and more particularly to a monomethylphytosphingosine (MMPS), which is a derivative of sphingoiipid, or a pharmaceutically acceptable salt thereof and a composition containing the same.

[2] Background Art

[3] Sphingoiipid was firstly found by Thudichum in 1884 and named as a sphinx like substance. It was known as a substance playing a substantial role in life phenomena as well as regulating cell growth, proliferation and differentiation.

[4] The sphingoiipid in a human body has sphingosine, phytosphingosine or sphinganine backbones and 300 or more kinds of derivatives including ceramide having fatty acids connected to the backbones.

[5] The sphingoiipid is a main ingredient constituting a cell membrane together with phospholipid and has polar and non-polar parts.

[6] Ceramide having a fatty acid connected to sphingoiipid is known as a substance playing an important role in causing various action mechanisms occurring in a cell. In particular, it takes part in a cell proliferation, a cell differentiation, a temporary growth arrest of the cell proliferation and an apoptosis.

[7] Since 1990's, functions of the sphingoiipid have been analyzed in earnest. In particular, the researches thereof have been actively performed as a protein kinase inhibiting efficacy of sphingosine was validated by Hannun and Bell, etc. In addition, as it was found that an important life phenomenon such as the cell differentiation, growth, aging and death is regulated by ceramide, it was become a core of a biology research.

[8] The ceramide is a substance causing an apoptosis which is an importance mechanism for a cancer treatment and thus development of an anti-cancer drug is focused on the ceramide. It is analyzed that many anti-cancer drugs, which are being currently used or developed, influence on a biosynthesis pathway of the ceramide and thus exhibit their effects.

[9] As a treatment for killing a cancer cell, ceramide and ceramide derivative and analog are directly treated to the cancer cell or a substance inducing or starting a de novo synthesis of ceramide may be used as an anti-cancer drug.

[10] Accordingly, since a substance regulating an activity of enzyme participating in biosynthesis of ceramide and sphingoiipid is highly possibly to be developed as an anti-cancer drug, it is recently taken intensive interests. Serine palmitoyl transferase (SPT), ceramidase, sphingomyeiinase (SMase), gluco-syiceramide (GlcCer) synthase and sphingosine kinase, etc. are enzymes participating in synthesis and hydrolysis of ceramide, and substances for activating and inhibiting such enzymes suggest a possibility of properly regulating a content of ceramide in a cancer cell and thus inducing an apoptosis of the cancer cell.

[11] Researches on substances regulating a content of ceramide in a cell can be confined to developments of derivatives and analogs of sphingoiipid and cermide and include many kinds of substances, for example, functional fatty acids, vitamins, androgen and ROS (reactive oxygen species: hydroxyperoxide, nitric oxide releasing compound) influencing on biosynthesis of sphingoiipid, and substances influencing on a glutathione (GSH) level and a lecithin level.

[12] Among them, P-drug, which has been actively researched as an anti-cancer drug in recent years, is a ceramide analog of aminoalcohols. PDMP (D-threo-l-phenyl-2-decanoylamino-3-mo holino-l-propanol) among them is an initial synthesis substance which is most developed and exhibits an excellent effect as an inhibitor of a synthesis of GlcCer (glucosylceramide) greatly influencing on a cell cycle. PPMP (D-1hreo-l-phenyl-2-palrnitoylamino-3-moφholino-l-propanol) having a better effect than PDMP is a homolog having a longer chain and PPPP (P4D-1hreo-l-phenyl-2-palrnitoylamino-3-pyrrolidino-l-propanol) is also an analog exhibiting an inhibitory effect higher than PDMP. The P-drug is expected to exhibit an anti-cancer effect for a general cancer cell and to inhibit a synthesis of GlcCer relating to tolerance to the anti-cancer drug, thereby contributing to a prevention of drug resistance.

[13] In addition, B13 or N-oleoylethanolamine, which are ceramidase inhibitors, is also a ceramide analog and inhibits a decomposition of the ceramide to induce a death of the cancer cell. Further, there are ceramide biosynthesis inhibitors having a structure similar to those of sphingoiipid and ceramide, such as FTY-720, fumonisin and myriosin, etc.

[14] There are many substances which have been already used as an anti-cancer drug, among the substances participating in the ceramide biosynthesis. Vincristine, gemcitabine, camptothecin, homocamptothecin, irinotecan, etc, are representative examples, most of which promote an activity of SMase. However, since GlcCer and sphingosine 1 -phosphate (SIP) produced from ceramide promote a cancer cell growth, it is expected that a development of a selective inhibitor of GlcCer synthase, ceramidase or sphingosine kinase (SPHK) will be an efficient treatment strategy for cancer. In particular, the SPHK inhibitor is a development target for a new anti-cancer drug and thus being recently researched.

[15] As a new anti-cancer target, many concerns have been recently focused on dimethylsphingosine (DMS) produced by methylation of sphingosine and safingol which is an isomer of sphinganine, which are known as a SPHK inhibitor. In fact, according to a study of a M.D. Anderson cancer research institute, the DMS was shown to have an efficacy for an acute leucosis exhibiting a drug resistance and a possibility of being developed into an anti-cancer drug was confirmed. In addition, researches on a specific structure capable of regulating contents of sphingoiipid and ceramide in a cell using such substances have been actively progressed.

[16] Disclosure of Invention Technical Problem

[17] Accordingly, the inventors applied various changes of a functional group to a basic structure of sphingoiipid and thus synthesized derivatives having a new structure, an anti-cancer efficacy and an improved solubility through a medical chemistry molecule design. As a result of that, it was validated that monomethylphytosphingosine (MMPS) exhibits an excellent ability of inhibiting an activity of sphingosine kinase and an anti- cancer efficacy.

[18] Accordingly, the present invention has been made to solve the above-mentioned problems occurring in the prior art. The object of the present invention is to inhibit an activity of sphingosine kinase using a derivative of sphingoiipid, i.e., a monomethylphytosphingosine (MMPS), to prevent ceramide and sphingosine from being phos- phorylated and thus to maintain concentrations of ceramide and sphingosine to be high, thereby inducing apoptosis of a cancer cell and thus treating or preventing a cancer or a cancer-related disease. Another object of the invention is to inhibit a cell proliferation- promoting activity of sphingosine kinase, thereby treating or preventing a hyper- proliferative disease such as a cancer and psoriasis. Still another object of the invention is to provide an anti-cancer composition having the above-mentioned efficacies.

[19] Technical Solution

[20] In order to accomplish the objects, there is provided a monomethylphytosphingosine (MMPS) having a following chemical formula 1 or a pharmaceutically acceptable salt thereof and a composition containing the same.

[21]

[22] ChemistryFigure 1 H

[23]

[24] AAccccoorrddiinnjg * ttoo tthe invention, there is provided a composition for inhibiting sphingosine kinase containing the monomethylphytosphingosine (MMPS) or a pharmaceutically acceptable salt thereof as an effective ingredient.

[25] In addition, the composition for inhibiting sphingosine kinase is used to treat or prevent a cancer or cancer-related disease.

[26] According to the invention, there is provided a composition for inducing apoptosis containing the monomethylphytosphingosine (MMPS) or a pharmaceutically acceptable salt thereof as an effective ingredient.

[27] In addition, the composition for inducing apoptosis is used to treat or prevent a cancer or cancer-related disease.

[28] According to the invention, there is provided a composition for treating or preventing a hyper-proliferative disease containing the monomethylphytosphingosine (MMPS) or a pharmaceutically acceptable salt thereof as an effective ingredient.

[29] In addition, the hyper-proliferative disease is psoriasis.

[30] According to the invention, there is provided an anti-cancer composition for treating or preventing a cancer containing the monomethylphytosphingosine (MMPS) or a pharmaceutically acceptable salt thereof as an effective ingredient.

[31] The composition of the invention containing the monomethylphytosphingosine- (MMPS) or a pharmaceutically acceptable salt thereof can be used in a medicine. The salt is not specifically limited if it is pharmaceutically acceptable. For example, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid, hy- drobromic acid, formic acid, acetic acid, tartaric acid, lactic acid, citric acid, fumaric acid, maleic acid, succinic acid, methane sulfonic acid, benzene sulfonic acid, toluene sulfonic acid and naphthalene sulfonic acid, etc. can be used.

[32] The monomethylphytosphingosine having the chemical formula 1 according to the invention can be prepared by formaldehyde-reacting phytosphingosine having a following chemical formula 2 in a solvent under the presence of a reducing agent.

[33] ChemistryFigure 2

[34] Advantageous Effects

[35] The MMPS and the pharmaceutically acceptable salt thereof according to the invention highly inhibits an activity of sphingosine kinase, to prevent ceramide and sphingosine from being phosphorylated and thus to maintain concentrations of ceramide and sphingosine to be high, thereby inducing apoptosis of a cancer cell and thus treating or preventing a cancer or a cancer-related disease. In addition, since the invention inhibits a cell proliferation-promoting activity of sphingosine kinase and thus exhibits an anti-cancer efficacy, the composition containing the same can be usefully used as a composition for inhibiting sphingosine kinase and an anti-cancer composition for treating or preventing a hyper-proliferative disease or a cancer.

[36] Brief Description of the Drawings

[37] FIG. 1 is a graph showing cytotoxicity of MMPS for MDA-MB-231 cells; and

[38] FIG. 2 is a graph showing a shpingosine kinase activity-inhibiting efficacy of MMPS.

[39] Best Mode for Carrying Out the Invention

[40] Hereinafter, the present invention will be more specifically described.

[41] The monomethylphytosphingosine having the chemical formula 1 of the invention can be prepared according to a following method. More specifically, the monomethylphytosphingosine having the chemical formula 1 can be prepared from the compound having the chemical formula 2 using a reductive methylation reaction applying an amine methylation reaction of protein. Firstly, a solvent prepared by mixing same amounts of borate buffer and methanol is added to phytosphingosine. After that, in order to increase a reactivity of amine, hydride, preferably sodium borohydride (NaBH ) of 8.0 to 10 mole based on the compound having the chemical formula 2 is added. Then, 35-37% water solution of formaldehyde is added several times by a predetermined amount at a time interval. Then, the mixture is reacted at a room temperature for 36-72 hours, so that it is possible to obtain the monomethylphytosphingosine having the chemical formula 1 of the invention.

[42] An oxidizing agent which can be used for the invention is not limited to the above mentioned. That is, it is possible to use all materials known in the art unless they influences on the reactions.

[43] In addition, the monomethylphytosphingosine having the chemical formula 1 prepared according to the above mentioned method is extracted using an organic solvent such as chloroform or a mixed solution of chloroform and methanol and then purified with an adsorption chromatography by silica gel.

[44] The purified monomethylphytosphingosine can be used in a medicine as it is or in a form of pharmaceutically acceptable salt. The salt is not specifically limited if it is pharmaceutically acceptable. For example, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid, hydrobromic acid, formic acid, acetic acid, tartaric acid, lactic acid, citric acid, fumaric acid, maleic acid, succinic acid, methane sulfonic acid, benzene sulfonic acid, toluene sulfonic acid and naphthalene sulfonic acid, etc. can be used.

[45] A pharmaceutical composition containing the monomethylphytosphingosine or the pharmaceutically acceptable salt thereof preferably contains 0.001 - 20 wt.% of the compound in a total composition. When the concentration is less than 0.001 wt.%, it is difficult to obtain the effect and when the concentration is more than 20 wt.%, it can cause an abnormality of a generative function.

[46] It can be expected a double anti-cancer effect of the monomethylphytosphingosine. That is, the monomethylphytosphingosine of the invention inhibits an activity of sphingosine kinase to induce an accumulation of ceramide and sphingosine, which promote a death of a cell, in a cell and interrupts a tumor inducing effect of sphingosine 1-phosphate (SIP) which is a product of sphingosine kinase.

[47] The inventors measured a sphingosine kinase inhibiting activity of the monomethylphytosphingosine having the chemical formula 1 which is a derivative of sphingoiipid, i.e., a methylation derivative of phytosphingosine. As a result of that, its efficacy was validated and it was also confirmed that the compound exhibited a sphingosine kinase inhibiting efficacy better than dimethylsphingosine (DMS).

[48] According to the invention, a pharmaceutical composition containing the monomethylphytosphingosine and the pharmaceutically acceptable salt thereof may further comprise proper carrier, excipient and diluent typically used to prepare the pharmaceutical composition.

[49] The compound of the invention can be pharmaceutically administrated in a form of a pharmaceutically acceptable salt thereof. Further, it can be administrated solely or in conjunction with and in a proper combination with other pharmaceutically acceptable active compounds.

[50] The pharmaceutical composition containing the compound of the invention can be used in forms of oral formulation such as acida, granulum, tablet, capsule, suspension, emulsion, syrup and aerosol, external preparations such as ointment and cream, suppository and sterilizing injection solution according to typical methods. Further, it can be formulated in any forms suitable for pharmaceutical preparations.

[51] Although a preferable dosage of the compound according to the invention varies with ages, sexes, weights, symptoms and degrees of diseases of administration subjects, drug forms, administration routes and administration periods, it can be properly selected by a skilled person in the art. However, considering a preferable effect, it is preferred that the compound of the invention is administrated in an amount of 0.001 - 1000 mg/kg per a day. The administration can be performed one time or many times per a day. In addition, the dosage can be increased or decreased according to the ages, sexes, weights, degrees of diseases and administration routes, etc. Accordingly, the dosage does not limit a scope of the invention in any way.

[52] The compound of the invention can be administrated to a mammal such as a rat, a mouse, a domestic animal and a human through various routes, for example, non-oral and oral administrations. All types of the administration can be expected. For instance, it can be administrated with oral, rectum or vein, muscle, hypodermic, and intrauterine dura mater or intracerebroventricular injections.

[53] Since the monomethylphytosphingosine and the salt containing the same according to the invention have little serious toxicity and side effect, they can be safely used for a prevention purpose for a long time.

[54] Mode for the Invention

[55] Hereinafter, the invention will be more specifically described with reference to examples and experimental examples. However, it should be noted that a scope of the invention is not limited to the examples in any way.

[56]

[57] Example 1: synthesis of monomethylph tosphingosine

[58] 200 ml of Methanol was added to 2 g of phytosphingosine (0.0063 mole) and then stirred and dissolved at 40 °C. After that, a solvent prepared by mixing same amounts of 0.2 M borate buffer (pH 9.0) and methanol was slowly added to the solution and then the mixture was dispersed with sonication. Then, 1 g of sodium borohydride was added in a 4 °C ice bath while paying attention to a boiling thereof. After 10 minutes, 37% water solution of formaldehyde was added six (6) times by 10 ml at a five (5) minute interval. After 24 hours, sodium borohydride was added once more in the same manner. The reaction was progressed at a room temperature for 72 hours only. After 72 hours, 100 ml of chloroform was added. The reaction was stopped with distilled water extraction. Then, it was obtained the monomethylphytosphingosine (MMPS) having the chemical formula 1 through an adsorption chromatography purification by silica gel. Then, the compound was again purified with silica gel thin layer chromatography (TLC) (development solvent: chloroform: methanol: ammonia water = 80: 20: 2, R = 0.6), thereby obtaining 1.5 g of monomethylphytosphingosine having the chemical formula 1 of white color (yield: 68.9%). In addition, it was confirmed that one methyl group was introduced with H NMR (Avance 500, Bruker) (d = 2.4 ppm, s, 3H). Further, a molecular weight thereof was measured and confirmed with MALDI-MASS (Applied biosystems INC, Voyag-DE ) (calculated value: 317.29, measured value: 316.35).

[59]

[60] Experimental example 1: measurement of cytotoxicity

[61] In order to examine a cytotoxicity of the monomethylphytosphingosine prepared according to the example 1, a MTT assay was performed as follows. MTT (3-[4,5-Dimethylthiazol-2yl]-2,5-diphenyltetrazolium) is a dyeing reagent exhibiting a yellow color when dissolving in a culture medium and has a characteristic that it is changed into a formazan with violet color by an active enzyme named as dehy- drogenase which exists in mitochondria of a living cell. Accordingly, since the color change into the formazan with violet color is reduced when a cell growth is stopped or the cell is dead, it is possible to evaluate cytotoxicity by measuring a degree of the color change through an absorbancy.

[62] Firstly, a human breast cancer cell line, i.e., MDA-MB-231 (obtained from Korea Institute of Radiological and Medical Sciences, Gongneung-dong, Seoul) was seeded to a 96- well p ^rlate in an amount of 1x10 cell/well and then cultured in a 5% CO 2 cultivator at 37 °C for 24 hours. Then, MMPS prepared according to the above example 1 and DMS (Dimethylsphingosine) were respectively diluted in serum free MEM, the cells were treated with 1 mM, 5 mM, 10 mM, 20 mM and 40 mM of the diluted MMPS and DMS and then cultured for 24 hours. After that, MTT having a final concentration of 0.5 mg/ml was put in each well and then further cultured for three (3) hours. Then, it was measured an absorbancy at 570 nm after dissolution of the dyeing reagent. At this time, a cell group, which was not treated with MMPS, was used as a negative control group and a cell group, which was treated with DMSO (Dimethylsulfoxide) having MMPS dissolved therein, was used as a solvent control group.

[63] As a result of that, as can be seen from Fig. 1, MMPS exhibited cytotoxicity almost similar to that of DMS at 20 mM and thus it was possible to determine an effective concentration of 10-20 mM.

[64]

[65] Experimental example 2: sphingosine kinase inhibiting efficacy of MMPS

[66] In order to measure a sphingosine kinase inhibiting efficacy of MMPS prepared according to the example 1, an experiment was performed as follows.

[67] Firstly, a sphingosine kinase activity assay was performed in a manner of 32 developing labeled sphingosine- 1-phosphate on TLC using P labeled ATP and then measuring a radiation dose. At this time, NEG 002 (2 mCi ml) of Perkin Elmer was used as the 32τ P labeled ATP and compositions of a buffered solution for sphingosine kinase assay were shown in the following Table 1 (SKI assay buffered solution was used). In addition, 1 mM PMSF and 0.5% aprotinin were used in a form of 50X stock solution prepared from protease inhibitor cocktail of Roche company, 200 mM DTT and 1M NaVO which is a phosphate inhibitor were added before using. The protease inhibitor and NaVO were used while keeping them at 4 °C and the DTT was used while keeping it at 20 °C.

[68] [69] Table 1

[70] [71] In sphingosine kinase assay, CHO-K1 (Chinese Hamster Ovary: ATCC Number: CCL-61, which is a cell line transfected with sphingosine kinase genes) cell lysate, substrate (10-40 mM), MMPS (10-100 mM) according to the example 1 which is a test sample, and ATP (0.5 mM, Hot 2uCi ml) were added to an E-tube and a buffered solution for the sphingosine kinase assay was added to the remaining to adapt a reaction volume. In addition, the lysate, which was taken out at -80 °C, was fused on ice, subject to sonication with 25-35A for 10 seconds, and then cooled for 5 seconds. This was repeated two times. After that, a proper amount thereof (which is determined after checking an expression level after the transfection) was added to the reaction solution and then an enzyme reaction was performed at 37 °C for 30 minutes. After the enzyme reaction was completed (reaction volume: 50 ml), 200 ml of a solution (chloroform: methanol: hydrochloric acid = 100: 200: 1) was added and subject to a vortex for one minute to complete the reaction. After that, 65 ml of chloroform and 650 ml of 1M KC1 solution were added to the solution, and subject to the vortex for 5 minutes and a centrifugal separation at 5, 000 rpm for three minutes, and then the resultant supernatant was completely removed and then evaporated. After the evaporation, 20 ml of a solution (chloroform: methanol = 2:1) was added and spot- dropped on the TLC plate. Then, development and exposure processes were performed using a solution (1-butanol: acetic acid: water = 3:1:1) as a development solution. After that, a radiation dose was measured to calculate a labeled sphingosine- 1-p). At this time, DMS was used as a control group.

[72] As a result of that, as can be seen from Fig. 2, MMPS (M-l) exhibited a sphingosine kinase inhibiting efficacy slightly superior to the positive control group of DMS.

[73] Formulation examples of the composition are set forth as follows. However, it should be noted that the examples are given only to illustrate the invention, not to limit it.

[74] [75] <Formulation example 1: MMPS 2% cream> [76] Table 2

[77] [78] Stearyl alcohol, cetyl alcohol, sorbitan monostearate and isopropyl myristate were introduced in a double- walled receptacle and then the mixture was heated until it was completely dissolved. The mixture was added to a mixture of purified water, propylene glycol and polysorbate 60 separately prepared using a liquid homogenizer at 70-75 °C. The produced emulsion was continuously mixed and cooled to below 25 °C. Subsequently, the solution of MMPS, polysorbate 80 and purified water and the anhydrous sodium sulfite solution in the purified water were added to the emulsion while continuously mixing the solutions. The cream was homogenized and filled in a proper tube.

[79] [80] <Formulation example 2: MMPS 2% local gel> [81] Table 3

[82] [83] A proper amount of hydrochloric acid was added to be a solution. A proper amount of sodium hydroxide was added to be pH 6.0. A proper amount of purified water was added to be 100 mg.

[84] MMPS was added to a solution of hydroxypropyl b-cyclodextrin in purified water while stirring it. Hydrochloric acid was added to be a solution and then sodium hydroxide was added to be pH 6.0. This solution was added to a dispersion solution of carrageenan PJ in propylene glycol while mixing it. The mixture was heated to 50 °C while slowly mixing, and added with ethyl alcohol and then cooled to about 35 °C. A remaining amount of purified water was added to the mixture and then the mixture was mixed to be homogeneous.

[85] [86] <Formulation example 3: MMPS nano-dispersion solution> [87] Table 4 MMPS nano-dispersion solution inversion phase

[88] [89] Migliol 812, MMPS and polysorbate 80 were mixed. Phosphatidyl choline was dissolved in ethanol and then added to the mixture to obtain a homogeneous clear liquid.

[90] [91] Table 5 MMPS nano-dispersion solution water phase

[92] [93] A water phase containing MMPS (for example, 94.54 g) was stirred and kept at 50 °C in a receptacle. A liquid nano-dispersion solution inversion phase (for example, 5.46 g) was stirred and added to the water phase.

[94] Industrial Applicability

[95] As described above, the MMPS and the pharmaceutically acceptable salt thereof according to the invention highly inhibits an activity of sphingosine kinase, to prevent ceramide and sphingosine from being phosphorylated and thus to maintain concentrations of ceramide and sphingosine to be high, thereby inducing apoptosis of a cancer cell and thus treating or preventing a cancer or a cancer-related disease. In addition, since the invention inhibits a cell proliferation-promoting activity of sphingosine kinase and thus exhibits an anti-cancer efficacy, the composition containing the same can be usefully used as a composition for inhibiting sphingosine kinase and an anti-cancer composition for treating or preventing a hyper-proliferative disease or a cancer.

Claims

[1] A monomethylphytosphingosine (MMPS) having a following chemical formula 1 or a pharmaceutically acceptable salt thereof. [Chemistry Figure 1] H

[2] A composition for inhibiting sphingosine kinase containing the monomethylphytosphingosine (MMPS) or the pharmaceutically acceptable salt thereof according to claim 1 as an effective ingredient.

[3] The composition according to claim 2, wherein the composition is used to treat or prevent a cancer or a cancer-related disease.

[4] A composition for inducing apoptosis containing the monomethylphytosphingosine (MMPS) or the pharmaceutically acceptable salt thereof according to claim 1 as an effective ingredient.

[5] The composition according to claim 4, wherein the composition is used to treat or prevent a cancer or a cancer-related disease.

[6] A composition for treating or preventing a hyper-proliferative disease containing the monomethylphytosphingosine (MMPS) or the pharmaceutically acceptable salt thereof according to claim 1 as an effective ingredient.

[7] The composition according to claim 6, wherein the hyper-proliferative disease is psoriasis.

[8] A composition for treating or preventing a cancer containing the monomethylphytosphingosine (MMPS) or the pharmaceutically acceptable salt thereof according to claim 1 as an effective ingredient.