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Anti-neoplastic pharmaceutical composition for targeting hedgehog pathway and cell autophagy

A technology of anti-tumor drugs and compositions, applied in the field of drugs, can solve the problems that have not yet been seen, and achieve the effect of extensive anti-tumor activity

Active Publication Date: 2016-08-24
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] At present, there is no clinical research report on the combination of hedgehog signaling pathway inhibitors and autophagy inhibitors as active ingredients or the combination of the two for anti-tumor

Method used

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  • Anti-neoplastic pharmaceutical composition for targeting hedgehog pathway and cell autophagy
  • Anti-neoplastic pharmaceutical composition for targeting hedgehog pathway and cell autophagy
  • Anti-neoplastic pharmaceutical composition for targeting hedgehog pathway and cell autophagy

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Example 1. Tumor cell culture

[0031] Tumor cells used in in vitro assays included lymphoma cells (Raji) and chronic myelogenous leukemia (CML) cells (K562, BaF3-BCR-ABL, BaF3-BCR-ABL T315I and BaF3-BCR-ABL Y253F ).

[0032] A special note is that: K562 is the most commonly used cell model in CML research, and it is sensitive to Imatinib, the first-line drug for clinical treatment of CML; while BaF3-BCR-ABL, BaF3-BCR-ABL T315I and BaF3-BCR-ABL Y253F Cells are the most common cell model used in the study of CML drug resistance, and the three strains of cells were respectively obtained by the following methods known in the art: the wild-type BCR-ABL gene, T315I site mutation, respectively, were transferred to BaF3 cells. The BCR-ABL gene and the BCR-ABL gene with the Y253F site mutation were obtained by establishing stable transfection cell lines; among them, BaF3-BCR-ABL cells are imatinib-sensitive cell lines, and BaF3-BCR-ABL cells are imatinib-sensitive cell lines...

Embodiment 2

[0034] Example 2. Preparation method of autophagy inhibitor in in vitro pharmacodynamic study

[0035] (1) Preparation of chloroquine: Dissolve an appropriate amount of chloroquine in double-distilled water to form a 10mmol / L storage solution, filter and sterilize with a 0.1 μm filter and store at 4°C. Dilute 500-1000 with cell culture medium for in vitro experiments. times for inhibiting autophagy;

[0036] (2) Preparation of hydroxychloroquine: Dissolve an appropriate amount of hydroxychloroquine in double distilled water to form a 10mmol / L storage solution, filter and sterilize with a 0.1 μm filter, store at 4°C, dilute 500-1000 times in an in vitro laboratory for use Inhibit autophagy;

[0037] (3) Preparation of bavalomycin A1: Take an appropriate amount of bavalomycin A1 dry powder to prepare a 0.5 μg / ml storage solution, filter and sterilize it with a 0.1 μm filter, store it at -20°C, and dilute it for in vitro experiments 1000 times for inhibiting autophagy;

[0038...

Embodiment 3

[0039] Example 3. Experiment of Hedgehog signaling pathway inhibitor vismodegib on growth inhibition of lymphoma and leukemia tumor cells

[0040] Vismodegib at 2.5, 5, 10, 20 and 40 μM was mixed with Raji, K562, BaF3-BCR-ABL, BaF3-BCR-ABL, respectively T315I and BaF3-BCR-ABL Y253F The cells were co-incubated for 48 hours, and the cell viability was detected by the CCK-8 method. The results showed that vismodegib could effectively reduce the viability of five kinds of tumor cells, and this growth inhibitory effect was dose-dependent (such as figure 1 shown).

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Abstract

The invention belongs to the field of medicine technology, and relates to an anti-tumor pharmaceutical composition targeting hedgehog pathway and autophagy. The drug has a significant synergistic effect in the treatment of solid tumors and non-solid tumors, especially has a very significant anti-tumor effect on drug-resistant chronic myelogenous leukemia. The pharmaceutical composition disclosed by the invention has extensive antitumor activity and has good clinical application prospect.

Description

technical field [0001] The invention belongs to the technical field of drugs, and relates to an anti-tumor pharmaceutical composition targeting hedgehog pathway and cell autophagy. The pharmaceutical composition comprises a Hedgehog signaling pathway inhibitor and a cell autophagy inhibitor, and can be used to treat solid tumors and non-solid tumors . Background technique [0002] The study revealed that the Hedgehog (Hh) signaling pathway is one of the main signaling pathways regulating animal embryonic development, plays a key role in the regulation of mammalian cell survival, proliferation and cell fate, and is currently one of the most concerned anti-tumor targets (Briscoe J, Thérond PP. [J]. Nat Rev Mol Cell Biol 2013, 14(7):418-431). More and more studies have shown that the abnormal activation of the Hh signaling pathway is closely related to basal cell carcinoma, leukemia, lymphoma, lung cancer, prostate cancer and digestive tract tumors (Briscoe J, Thérond PP.[J].N...

Claims

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Application Information

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IPC IPC(8): A61K45/06A61P35/00
Inventor 鞠佃文曾贤赵荟李玉彬范佳君王子玉王绍飞宋平
Owner FUDAN UNIV
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