CN113197905B - Application of triterpenoid in preparation of medicine for treating neuroblastoma - Google Patents
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- 206010029260 Neuroblastoma Diseases 0.000 title claims abstract description 29
- 239000003814 drug Substances 0.000 title claims abstract description 10
- XBZYWSMVVKYHQN-MYPRUECHSA-N (4as,6as,6br,8ar,9r,10s,12ar,12br,14bs)-10-hydroxy-2,2,6a,6b,9,12a-hexamethyl-9-[(sulfooxy)methyl]-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-4a-carboxylic acid Chemical compound C1C[C@H](O)[C@@](C)(COS(O)(=O)=O)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CCC(C)(C)C[C@H]5C4=CC[C@@H]3[C@]21C XBZYWSMVVKYHQN-MYPRUECHSA-N 0.000 title description 4
- 238000002360 preparation method Methods 0.000 title description 4
- -1 triterpenoid compound Chemical class 0.000 claims abstract description 6
- FICQFRCPSFCFBY-UHFFFAOYSA-N 2-[bis(methylsulfanyl)methylidene]propanedinitrile Chemical compound CSC(SC)=C(C#N)C#N FICQFRCPSFCFBY-UHFFFAOYSA-N 0.000 claims abstract description 3
- 239000000126 substance Substances 0.000 claims abstract description 3
- SUBDBMMJDZJVOS-UHFFFAOYSA-N 5-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-UHFFFAOYSA-N 0.000 claims description 2
- 229960000381 omeprazole Drugs 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 150000003648 triterpenes Chemical class 0.000 claims description 2
- 229940124531 pharmaceutical excipient Drugs 0.000 claims 1
- 210000004027 cell Anatomy 0.000 abstract description 23
- 150000001875 compounds Chemical class 0.000 abstract description 14
- 230000000694 effects Effects 0.000 abstract description 8
- 230000035755 proliferation Effects 0.000 abstract description 7
- 230000004083 survival effect Effects 0.000 abstract description 7
- 238000011282 treatment Methods 0.000 abstract description 7
- 230000003021 clonogenic effect Effects 0.000 abstract description 5
- 238000004393 prognosis Methods 0.000 abstract description 5
- 230000005764 inhibitory process Effects 0.000 abstract description 4
- 210000004881 tumor cell Anatomy 0.000 abstract description 3
- 201000010099 disease Diseases 0.000 abstract description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 2
- 238000000034 method Methods 0.000 abstract description 2
- RJCWBNBKOKFWNY-IDPLTSGASA-N n-[(4as,6ar,6bs,8ar,12as,14ar,14bs)-11-cyano-2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-1,3,4,5,6,7,8,8a,14a,14b-decahydropicen-4a-yl]-2,2-difluoropropanamide Chemical compound C([C@@]12C)=C(C#N)C(=O)C(C)(C)[C@@H]1CC[C@]1(C)C2=CC(=O)[C@@H]2[C@@H]3CC(C)(C)CC[C@]3(NC(=O)C(F)(F)C)CC[C@]21C RJCWBNBKOKFWNY-IDPLTSGASA-N 0.000 abstract 3
- 230000002401 inhibitory effect Effects 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 4
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 4
- 229960004316 cisplatin Drugs 0.000 description 4
- IOOMXAQUNPWDLL-UHFFFAOYSA-N 2-[6-(diethylamino)-3-(diethyliminiumyl)-3h-xanthen-9-yl]-5-sulfobenzene-1-sulfonate Chemical compound C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=C(S(O)(=O)=O)C=C1S([O-])(=O)=O IOOMXAQUNPWDLL-UHFFFAOYSA-N 0.000 description 3
- 230000004544 DNA amplification Effects 0.000 description 3
- 101150022024 MYCN gene Proteins 0.000 description 2
- 230000009471 action Effects 0.000 description 2
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- 229940079593 drug Drugs 0.000 description 2
- 238000010832 independent-sample T-test Methods 0.000 description 2
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- 206010003591 Ataxia Diseases 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
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- 101000588302 Homo sapiens Nuclear factor erythroid 2-related factor 2 Proteins 0.000 description 1
- 102000004034 Kelch-Like ECH-Associated Protein 1 Human genes 0.000 description 1
- 108090000484 Kelch-Like ECH-Associated Protein 1 Proteins 0.000 description 1
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- 210000001943 adrenal medulla Anatomy 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
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- 229940044683 chemotherapy drug Drugs 0.000 description 1
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- 206010015037 epilepsy Diseases 0.000 description 1
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- 239000007788 liquid Substances 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 230000004898 mitochondrial function Effects 0.000 description 1
- 238000010369 molecular cloning Methods 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 210000000933 neural crest Anatomy 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- 208000029255 peripheral nervous system cancer Diseases 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 230000007076 release of cytoplasmic sequestered NF-kappaB Effects 0.000 description 1
- 210000000844 retinal pigment epithelial cell Anatomy 0.000 description 1
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- 230000002889 sympathetic effect Effects 0.000 description 1
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- 239000003826 tablet Substances 0.000 description 1
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- 230000005748 tumor development Effects 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract
The invention provides an application of a triterpenoid compound in preparing a neuroblastoma medicament, wherein the triterpenoid compound is ormolone (RTA-408) with a chemical name of: n- (2-cyano-3, 12-dioxo-28-norolean-1, 9(11) -dien-17-yl) -2, 2-difluoropropionamide with molecular formula C33H44F2N2O3. The compound RTA-408 can generate obvious proliferation inhibition effect on neuroblastoma passage cells and patient-derived tumor cells (PDC), and obviously inhibit the clonogenic capacity of neuroblastoma cells. The invention provides a brand-new treatment means for clinical treatment of neuroblastoma and also expands the application range of RTA-408 in clinical disease treatment. Meanwhile, the method provides possibility for further improving the clinical curative effect of the patient with neuroblastoma and improving the prognosis and survival of the patient.
Description
Technical Field
The invention belongs to the application field of compounds, and relates to application of triterpenoids in preparation of a medicine for treating neuroblastoma, wherein the compounds are ormolone (RTA-408).
Background
Neuroblastoma is a type of malignant tumor of the peripheral nervous system originating from the sympathetic nerves of the neural crest, the most common and deadliest extracranial solid tumor in infants and young children, with about 90% of patients diagnosed to be no older than 5 years of age. Primary neuroblastoma is often located in tissues of sympathetic nervous system, adrenal medulla, or paraspinal ganglion origin. Neuroblastoma can be classified into low-risk type, medium-risk type and high-risk type according to the risk rating, the prognosis of low-risk type and medium-risk type patients is usually better (the survival rate without events is about 80% -95%), but high-risk type patients have quick disease progression due to molecular characteristics such as MYCN gene amplification, ALK gene amplification or mutation, Trk abnormal expression and the like, the clinical cure rate is lower than 35%, and the prognosis and survival conditions are not optimistic. Therefore, the development of new effective therapeutic drugs is still required for the clinical treatment of neuroblastoma.
The triterpenoid RTA-408 was developed to inhibit KEAP1 protein and activate the antioxidant protein NRF2 signaling pathway to reduce inflammatory response by restoring mitochondrial function, reducing oxidative stress and inhibiting pro-inflammatory signals. Several clinical trials of anti-inflammatory treatments are currently being conducted on compound RTA-408, including autoimmune encephalomyelitis, retinal pigment epithelial cell damage and epilepsy. Notably, RTA-408 was granted by the european medicines agency as the first approved therapy for the treatment of friedrichs' ataxia. In addition, studies report that RTA-408 can inhibit the activation of NF-kappa B, an important signal pathway for tumor development, and relevant clinical trials have investigated the anti-tumor therapeutic effect of RTA-408 on patients with melanoma and non-small cell lung cancer. However, it has not been reported that RTA-408 can inhibit the proliferation and clonogenic ability of neuroblastoma and thereby improve the survival and prognosis of neuroblastoma patients.
Disclosure of Invention
The invention aims to provide application of a triterpenoid compound in preparing a medicine for treating neuroblastoma, wherein the triterpenoid compound is omeprazole (RTA-408) with the chemical name: n- (2-cyano-3, 12-dioxo-28-norolean-1, 9(11) -dien-17-yl) -2, 2-difluoropropionamide with molecular formula C33H44F2N2O3. The medicine is prepared from triterpenoid and pharmaceutic adjuvant.
The compound RTA-408 can generate obvious proliferation inhibition effect on both neuroblastoma passage cells and tumor cells PDC, and can also obviously inhibit the clone formation capability of neuroblastoma cells. In addition, compared with the traditional chemotherapeutic drug cisplatin, the effect of RTA-408 in inhibiting the clonogenic capacity of neuroblastoma cells is more remarkable.
The invention provides the application of the compound RTA-408 as a brand-new intervention means for treating neuroblastoma, expands the application range of RTA-408 in clinical disease treatment, and provides possibility for further improving the clinical curative effect of neuroblastoma patients and improving the prognosis and survival of neuroblastoma patients.
Drawings
FIG. 1 shows the inhibitory effect of compound RTA-408 at different concentrations on the proliferation of five neuroblastoma cell lines SK-N-DZ, SK-N-BE (2), IMR-32, SK-N-SH and SH-SY5Y, wherein the SK-N-DZ, SK-N-BE (2) and IMR-32 cells have the characteristic of MYCN gene amplification.
FIG. 2 shows the inhibitory effect of compound RTA-408 at different concentrations on the clonogenic capacity of the neuroblastoma cell lines SK-N-DZ and SK-N-BE (2).
FIG. 3 shows the inhibitory effect of compound RTA-408 at various concentrations on the proliferation of tumor cells derived from patients with neuroblastoma.
In the figure, Control group and RTA-408 were administeredThe comparison between groups was performed using independent samples t test: n.s means p > 0.05; p < 0.05; p < 0.01; p < 0.001. The comparison between the cisplatin-administered group and the RTA-408 administered group was also performed using independent sample t-test: n.s means p > 0.05;###p is < 0.001.
Detailed Description
The present invention will be described in further detail with reference to the accompanying drawings and examples. The following examples are intended to illustrate the invention only and are not intended to limit the scope of the invention.
The experimental procedures, for which specific conditions are not indicated in the examples, are generally carried out according to conventional conditions, for example as described in Sambrook et al, molecular cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press,1989), or according to the conditions as recommended by the manufacturer.
The application of the compound RTA-408 of the invention can refer to the conventional drug configuration method and actual development. The pharmaceutical and biological preparations are any medically approved dosage forms, such as powder, injection, capsule, tablet or oral liquid.
Example 1
SK-N-DZ, SK-N-BE (2), IMR-32, SK-N-SH and SH-SY5Y cells were seeded in 96-well plates at a density of 5000 cells per well, with varying concentrations of compound RTA-408 (6.25X 10)-8～2×10-6M) treating the cells respectively, setting 3 multiple holes for each concentration action group, and detecting the survival condition of the cells by a sulforhodamine B (SRB) staining method after RTA-408 is acted for 72 hours. The results show that 2.5X 10-7～2×10-6RTA-408 with M concentration range has obvious proliferation inhibition effect on five neuroblastoma cell strains. Half Inhibitory Concentration (IC) of RTA-408 against SK-N-DZ, SK-N-BE (2), IMR-32, SK-N-SH and SH-SY5Y cell lines50) 475. + -.9 nM, 484. + -.13 nM, 174. + -.16 nM, 677. + -.138 nM and 478. + -.18 nM, respectively. The results are shown in FIG. 1.
Example 2
SK-N-DZ and SK-N-BE (2) cells were seeded in 6-well plates at a density of 10000 per well, with different concentrations of cisplatin and RTA-408 (6.25X 10)-8～1×10-6M) treating the cells respectively, culturing for 10-14 days, observing the cell clone number, and calculating the clone formation rate. The results show that the compound RTA-408 (1.25X 10)-7～1×10-6M) has obvious inhibition effect on the clone formation capability of SK-N-DZ and SK-N-BE (2) cells; cisplatin can also inhibit the clonogenic capacity of SK-N-DZ and SK-N-BE (2) cells to some extent, but at the same concentration (2.5X 10)-7～1×10-6M), the effect of the compound RTA-408 in inhibiting the cell clone formation capability of SK-N-DZ and SK-N-BE (2) is obviously stronger than that of cisplatin. The results are shown in FIG. 2.
Example 3
Three neuroblastoma PDC s were seeded at a density of 3000 cells per well in 96-well plates, with different concentrations of compound RTA-408 (3.125X 10)-8～1×10-6M) the cells were treated separately, 3 multiple wells were set for each concentration group, and the survival of the cells was examined by SRB staining after 72 hours of RTA-408 action. The results showed 6.25X 10-8～1×10-6RTA-408 in the M concentration range can obviously inhibit the proliferation of three neuroblastoma PDC. IC of RTA-408 to three neuroblastoma PDC50265.0nM, 188.4nM and 292.8nM, respectively. The results are shown in FIG. 3.
Claims (2)
1. The application of a triterpenoid compound in preparing a medicine for treating neuroblastoma is characterized in that the triterpenoid compound is omeprazole, and the chemical name is as follows: n- (2-cyano-3, 12-dioxo-28-norolean-1, 9(11) -dien-17-yl) -2, 2-difluoropropionamide with molecular formula C33H44F2N2O3。
2. The use according to claim 1, wherein the medicament is prepared from triterpenoids in pharmaceutical excipients.
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| CN105324389A (en) * | 2013-04-24 | 2016-02-10 | 艾伯维公司 | 2,2-difluoropropionamide derivatives of bardoxolone methyl, polymorphic forms and methods of use thereof |
| CA2984407A1 (en) * | 2016-11-04 | 2018-05-04 | Stealth Biotherapeutics Corp | Therapeutic compositions including triterpenoid and uses thereof to treat and prevent mitochondrial diseases and conditions |
| JP2018131429A (en) * | 2017-02-14 | 2018-08-23 | 拓己 佐藤 | Use of organic acid as method to enhance effect of nrf2 activator |
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2021
- 2021-04-23 CN CN202110438929.2A patent/CN113197905B/en active Active
Patent Citations (5)
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| CN104395332A (en) * | 2012-04-27 | 2015-03-04 | 里亚塔医药公司 | 2.2-difluoropropionamide derivatives of bardoxolone methyl, polymorphic forms and methods of use thereof |
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