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Use of canagliflozin in the preparation of medicines for treating diseases mediated by tuberous sclerosis

A technology for tuberous sclerosis and disease medicine, which is applied in the field of disease treatment and prevention, tuberous sclerosis treatment and related medicines, and can solve unfavorable treatment, no treatment effect, and no particularly effective treatment of pulmonary lymphangioleiomyoma. methods, etc.

Active Publication Date: 2022-04-08
SIR RUN RUN HOSPITAL NANJING MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, there is no mature pathological diagnosis of pulmonary lymphangioleiomyomatosis. Except for the positive HMB 45 antibody related to melanoma, the positive estrogen receptor (ER) and progesterone receptor (PR) are the marker antibodies of LAM. And the newly discovered cathepsin-k (Cathepsin-k) in recent years is also one of the auxiliary molecular markers for its diagnosis
[0015] At the same time, there is no particularly effective method for the treatment of pulmonary lymphangioleiomyoma at this stage, mainly drug control and lung transplantation
[0016] In the clinical treatment of pulmonary lymphangioleiomyomatosis mediated by tuberous sclerosis, the macrolide antibiotic rapamycin (rapamycin) is a drug discovered in recent years that can effectively control tumor progression. The target is the mTORC1 protein complex in the mTOR signaling pathway, but after the patient stops using rapamycin, the tumor relapses in a short period of time, and there is no therapeutic effect in some patients with sporadic pulmonary lymphangioleiomyoma
Pulmonary lymphangioleiomyoma, like most malignant tumors, is not conducive to the treatment of the disease with a single therapeutic target

Method used

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  • Use of canagliflozin in the preparation of medicines for treating diseases mediated by tuberous sclerosis
  • Use of canagliflozin in the preparation of medicines for treating diseases mediated by tuberous sclerosis
  • Use of canagliflozin in the preparation of medicines for treating diseases mediated by tuberous sclerosis

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] 10 per well of 96-well plate 4 TSC2 - / - For MEF cells, adhere to the wall for 12-24 hours. Drugs of different concentrations were added according to the experimental groups, each group had at least 6 replicate wells, and the effect was 48 hours. After drug treatment, add 10 μL of CCK8 solution to 100 μL of serum-free medium in each well, incubate in a 37°C incubator for 1 hour, carefully suck out the medium, and detect its absorbance at a wavelength of 450 nm with a microplate reader.

[0066] This experiment is divided into 10 groups, which are the control group, canagliflozin 0, 16777.2, 20971.5, 26214.4, 32768, 40960, 51200, 64000, 80000 and 100000nM groups, and the control group is the solvent DMSO of canagliflozin. for TSC2 - / - MEF cells were treated for 48 hours under normal culture conditions of DMEM+10% FBS.

[0067] Such as figure 1 As shown, canagliflozin can inhibit TSC2 concentration-dependently - / - Cell activity, IC50 is 53.93μM, 40Mm equivalent clini...

Embodiment 2

[0069] 10 per well of 96-well plate 4 TSC2 - / - For MEF cells, adhere to the wall for 12-24 hours. Drugs of different concentrations were added according to the experimental groups, each group had at least 6 replicate wells, and the effect was 48 hours. After drug treatment, add 10 μL of CCK8 solution to 100 μL of serum-free medium in each well, incubate in a 37°C incubator for 1 hour, carefully suck out the medium, and detect its absorbance at a wavelength of 450 nm with a microplate reader.

[0070] This experiment is divided into three groups, namely the control group, canagliflozin 20μM, 30μM, 40μM groups, in which the control group is the solvent DMSO of canagliflozin, and the cells are TSC2 - / - MEF cells were treated for 48 hours under normal culture conditions of DMEM+10% FBS.

[0071] Depend on figure 2 It can be seen that as the concentration of canagliflozin becomes higher and higher, the proliferation activity of cells becomes lower and lower, and compared with ...

Embodiment 3

[0073] Dilute the Binding Buffer (10×) into 1× Binding Buffer Working Solution for later use (1ml of Binding Buffer (10×) needs to be added to 9mL of sterile deionized water). Digest TSC2 with EDTA-free trypsin - / - For the cells, add the cell culture medium, blow the cells down gently, transfer them to a centrifuge tube, and collect the cells by centrifugation at 500-1000g for 5 minutes. After collecting the cells, add pre-cooled PBS solution and gently blow and wash with a pipette, collect the cells by centrifugation, and wash twice in total. Add 1× binding buffer working solution to the cell pellet, resuspend the cells, and make the cell concentration reach 1×10 6 cells / mL. Aspirate 100 μL of cell suspension (the total number of cells is 1×10 5 cells) into a new tube, add 5uL Annexin V-FITC and 5uL PI, mix gently, and incubate at room temperature for 15min in the dark. After staining and incubation, add 400Ul 1× binding buffer working solution to each tube, mix well and ...

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Abstract

The invention discloses the use of canagliflozin in the preparation of medicines for treating diseases mediated by tuberous sclerosis. Canagliflozin can selectively target TSC mutant cells, significantly affect the viability of TSC mutant cells, and promote TSC mutation apoptosis.

Description

technical field [0001] The invention relates to the field of treatment and prevention of diseases mediated by tuberous sclerosis, and belongs to the field of treatment of tuberous sclerosis and related medicines. Background technique [0002] Tuberous sclerosis (TSC), also known as Boumeville disease, is a multisystem genetic disease, an autosomal dominant disease, with a global incidence of 1 / 6000-10000. It is estimated that more than 1 million people are affected worldwide. The pathogenesis of tuberous sclerosis is mainly the mutation of the tumor suppressor gene TSC1 and / or TSC2. Mutations in either of these two genes will lead to the clinical manifestations of tuberous sclerosis, that is, mutations in the two genes TSC1 and TSC2 There is a causal relationship with the development of TSC. The proteins encoded by TSC2 / TSC1, hamartin and tuberin, can regulate the expression of mTOR (mammaliantarget of rapamycin) signaling pathway. Mammalian target of rapamycin (mTOR) is ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/381A61K31/436A61K31/4178A61K31/506A61P25/00A61P13/12A61P35/00A61P17/00A61P27/02A61P19/08
CPCA61K31/381A61K31/436A61K31/4178A61K31/506A61P25/00A61P13/12A61P35/00A61P17/00A61P27/02A61P19/08A61K2300/00
Inventor 薛斌叶娟曹鹏吴菁
Owner SIR RUN RUN HOSPITAL NANJING MEDICAL UNIV
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