Synergistic tumor inhibition composition and application thereof

A technology of tumor suppression and composition, applied in the field of pharmacy, can solve problems that cannot be explained and need further research

Active Publication Date: 2020-05-29
CENT FOR EXCELLENCE IN MOLECULAR CELL SCI CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This also cannot explain how even a small dose of MTA in the clinic can target a small part of the dividing cells in the tumor, so that the tumor with a very slow growth rate, such as breast cancer, can regress in a large area
Overall, the mechanism by which MTA promotes tumor regression remains to be further investigated

Method used

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  • Synergistic tumor inhibition composition and application thereof
  • Synergistic tumor inhibition composition and application thereof
  • Synergistic tumor inhibition composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0208] Example 1, the mechanism of action of microtubule-targeting drug (MTA) causing cell necrosis in fibrosarcoma cells

[0209] Fibrosarcoma cells (L929) are a murine fibrosarcoma cell line that is very sensitive to TNF. After being stimulated by recombinant TNF, they can undergo membrane lytic death through programmed cell necrosis (hereinafter referred to as "cell necrosis"). The inventors used the sensitivity of L929 to TNF stimulation to establish a stable cell necrosis experimental system, trying to find necrosis inhibitors through large-scale compound screening. Unexpectedly, the present inventors discovered that microtubule-targeting drugs (MTA)—such as microtubule depolymerization drugs (Nocodazole, NCZ; Vincristine, VCR) and microtubule stabilization Docetaxel / docetaxel (Docetaxel, DTX) can directly induce necrosis of L929 cells, and this effect is concentration-dependent and can be inhibited by necrosis-specific inhibitor Nec-1. blocking ( figure 1 a). In Rip1 ...

Embodiment 2

[0216] Example 2, The necrosis caused by MTA in L929 cells is mediated by membrane-localized TNF

[0217] The inventor constructed the L929 cell line of Tnf gene knockout, and found that the cell necrosis caused by MTA was blocked ( image 3 a). This data is consistent with the results of Tnfr1 knockout in Example 1.

[0218] Furthermore, by neutralizing with an antibody against TNF, the inventors found that MTA-induced necrosis was largely suppressed ( image 3 b). Therefore, it was determined that the cell necrosis induced by MTA on L929 was mediated by TNF.

[0219] Raw264.7 cells and L929 cells were stimulated with LPS and NCZ respectively, and then the culture supernatant (CM) was taken to treat fresh L929 cells, and cell necrosis was detected within 12 hours. The inventors found that fresh L929 cells were very sensitive to activated Raw264.7 culture supernatant, and could undergo membrane lytic necrosis, but they did not respond to NCZ-treated L929 culture supernatan...

Embodiment 3

[0223] Example 3, MTA stimulates memTNF transcription through the JNK-cJun pathway

[0224] In order to further explore the mechanism of MTA regulating memTNF, first, the inventors detected whether the expression of TNF was activated at the transcriptional level after MTA treatment. The inventors found that the transcription inhibitor actinomycin D (ActD) can completely block the cell necrosis caused by NCZ and PTX ( Figure 4 a), indicating that MTA activates the transcription of Tnf gene. Real-time quantitative PCR results showed that after NCZ and PTX treatment, Tnf mRNA levels were upregulated over time ( Figure 4 b).

[0225] In order to find the transcription factor that regulates the expression of TNF after MTA stimulation, the inventors used L929 treated with MTA to perform RNA sequencing analysis. The results first verified that NCZ / PTX treatment activated the expression of endogenous TnfmRNA, after 3 hours and 16 hours of treatment , Tnf mRNA levels increased ove...

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Abstract

The invention relates to a synergistic tumor inhibition composition and application thereof. A molecular mechanism of microtubule-targeting agents (MTAs) in a process of triggering programmed cell death of tumor cells is provided for the first time, a JNK-cJun pathway is utilized to excite a membrane to locate the transcription of TNF (membrane-bound TNF, mTNF), the membrane localization TNF further activates apoptosis or necrosis of a death receptor TNFR1 and an initial cell, and the molecular mechanism can be used as an anti-tumor targeting drug taking the membrane- localization TNF as a target and can be used for developing a drug for promoting the efficacy of MTAs drugs. The invention also discloses a novel pharmaceutical composition scheme, namely combining MTAs drugs and IAP inhibitors (such as Smac mimics (SM), i.e., Smac analogues), tumor cell apoptosis induced by MTAs drugs and caused by membrane localization TNF up-regulation can be greatly promoted, and the effective dose and the medication time of the MTAs drugs are reduced so that the toxic and side effects of the chemotherapeutic drugs are reduced.

Description

technical field [0001] The invention belongs to the field of pharmacy, and more specifically, the invention relates to a synergistic tumor suppressing composition and application thereof. Background technique [0002] Microtubule-targeting agent (MTA) is a class of widely used chemotherapeutic drugs, which has achieved great success in clinic for a long time. Although it has been well verified in the clinical treatment of tumors, the mechanism of MTA-induced tumor cell death remains unanswered. [0003] Microtubule is the target of MTA, which plays an important role in both dividing cells and non-dividing cells. MTA interferes with microtubule polymerization (microtubule depolymerizers, such as colchicine and vinca alkaloids, etc.) or stabilizes microtubule polymers (microtubule stabilizers, such as taxanes and epothiloes, etc.) to play a role. [0004] In recent years, the theory that MTA kills cancer cells by inducing mitotic arrest has been increasingly questioned. A ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): G01N33/50A61K45/06A61P35/00
CPCG01N33/5011A61K45/06A61P35/00
Inventor 孙丽明张晶
Owner CENT FOR EXCELLENCE IN MOLECULAR CELL SCI CHINESE ACAD OF SCI
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