Application of egfr inhibitors in the preparation of drugs for the treatment of muc1 positive tumors

A technology of MUC1-EGFR-ABCB1 and tumor drugs, applied in the field of tumor treatment, can solve problems such as limited treatment methods, increased mortality, and difficulty in early diagnosis of lung cancer, and achieve the effect of inhibiting cell proliferation, preventing recurrence, and controlling growth

Active Publication Date: 2022-07-29
SHANGHAI JIAOTONG UNIV SCHOOL OF MEDICINE
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

And with the changes in the environment and lifestyles caused by the industrialization process, the incidence of lung cancer is increasing every year, and due to the difficulty in early diagnosis of lung cancer and limited treatment methods, the mortality rate is also rising

Method used

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  • Application of egfr inhibitors in the preparation of drugs for the treatment of muc1 positive tumors
  • Application of egfr inhibitors in the preparation of drugs for the treatment of muc1 positive tumors
  • Application of egfr inhibitors in the preparation of drugs for the treatment of muc1 positive tumors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Example 1. MUC1 modulates chemotherapeutic drug sensitivity of tumor cells.

[0045] To investigate the role of MUC1 in cervical cancer and lung mucoepidermoid carcinogenesis, we firstly transferred pRNAU6.1-CTL shRNA and two pRNAU6.1-MUC1 shRNA-A, pRNAU6 into cervical cancer and lung mucoepidermoid carcinoma line HeLa229 .1-MUC1 shRNA-B plasmid, positive clones were screened by G418 resistance, and the expression of MUC1 was detected by Western Blot. Western Blot results showed that we obtained two HeLa229 / shCTL and two HeLa229 / shMUC1 strains each ( figure 1 A). Using these four cell lines, we examined the role of MUC1 in the tolerance of commonly used drugs in small cell chemotherapy. The results show that in Paclitaxel ( figure 1 B), vincristine (Vincristine) ( figure 1 C), Doxorubicin (Doxorubicin) ( figure 1 D) and etoposide (Etoposide) ( figure 1 E) Among the four drugs, the cell viability of HeLa229 / shMUC1 was significantly reduced compared with HeLa229 / shC...

Embodiment 2

[0046]Example 2. The expression of MUC1 is up-regulated in the process of acquired drug resistance of tumor cells.

[0047] To demonstrate the regulatory role of MUC1 on chemosensitivity in tumor cells, we examined the expression of MUC1 in response to paclitaxel. The results showed that under the action of paclitaxel for a short time in HeLa229 cells, MUC1 mRNA ( figure 2 A) and protein levels ( figure 2 B) were significantly increased. We further constructed paclitaxel-resistant cell lines: HeLa229 / TR and NCI-H292 / TR. The detection of the two cell lines found that compared with the parent cell line, HeLa229 / TR ( figure 2 C) and NCI-H292 / TR ( figure 2 D) MUC1 mRNA and protein levels were significantly increased in cells. On the one hand, it shows that the chemotherapeutic drug paclitaxel up-regulates the level of MUC1 mRNA, thereby increasing the protein expression of MUC1, and on the other hand, it shows that MUC1 may be necessary for cell drug resistance. To prove...

Embodiment 3

[0048] Example 3. MUC1 induces drug resistance by regulating ABCB1.

[0049] To further study the drug resistance mechanism of MUC1, we examined the expression of ABC family protein member ABCB1, which is closely related to drug resistance. The results show that in HeLa229 ( image 3 A) and NCI-H292 ( image 3 B) The mRNA and protein expression levels of the drug-resistant strain ABCB1 were significantly increased. HeLa229 / TR and NCI-H292 / TR cells were infected with pGIZ-Puromycin lentivirus containing shMUC1 to silence the MUC1 gene, and the mRNA and protein expression levels of ABCB1 were detected by Q-PCR and Western Blot. The results showed that after silencing MUC1, HeLa229 / TR ( image 3 C) and NCI-H292 / TR ( image 3 The mRNA and protein expression of ABCB1 in D) decreased, indicating that MUC1 directly regulates the expression of ABCB1. To further verify the role of ABCB1 in cell drug resistance, we used ABCB1 inhibitors Verapamil or Zosuquidar in combination with p...

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Abstract

The invention discloses an application of an EGFR inhibitor in the preparation of a drug for the treatment of MUC1-positive tumors, and relates to the application of an inhibitor targeting the MUC1-EGFR-ABCB1 signaling pathway in combination with an ABCB1 substrate chemotherapeutic drug in the preparation of a drug for the treatment of MUC1-positive tumors. The present invention discloses the molecular mechanism by which chemotherapeutic drugs induce MUC1 expression and activate the MUC1-EGFR-ABCB1 signaling pathway in cervical cancer and lung mucoepidermoid cancer, and finally cause cells to pump the drugs out of the membrane to produce drug resistance. At the same time, targeted inhibition of EGFR can effectively inhibit the proliferation of cervical cancer and lung mucoepidermoid cancer cells, control the growth of transplanted tumors, and effectively prevent the recurrence of transplanted tumors. It is suggested that the combination of inhibitors targeting MUC1-EGFR-ABCB1 signaling pathway and ABCB1 substrate chemotherapeutic drugs has broad prospects in the preparation of MUC1-positive tumor drugs.

Description

technical field [0001] The invention belongs to the field of tumor treatment, and more particularly relates to the application of an inhibitor targeting the MUC1-EGFR-ABCB1 signaling pathway in the preparation of a medicament for treating MUC1-positive tumors. Background technique [0002] Tumor therapy is often accompanied by drug resistance and tumor recurrence. The overexpression of ATP-binding cassettes (ABCs) in tumor cells is the main reason why tumor cells acquire multidrug resistance and lead to drug resistance. ABCs are a class of ATP-dependent transporters that selectively pump substrates, including drugs, out of cells. Among them, ABCB1, also known as P-glycoprotein or multidrug resistance protein 1 (MDR1), is often found to be overexpressed in tumors. Many drugs used in tumor therapy such as Paclitaxel, Vincristine, Doxorubicin and Etoposide are all substrates of ABCB1. Therefore, overexpression of ABCB1 is an important cause of tumor resistance. [0003] Epid...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K45/06A61K31/337A61K31/475A61K31/704A61K31/7048A61K31/277A61K31/713A61K31/5377A61K31/517A61K31/519A61K31/506A61K31/4709A61P35/00A61P35/04
CPCA61K45/06A61K31/277A61K31/337A61K31/4709A61K31/475A61K31/506A61K31/517A61K31/519A61K31/5377A61K31/704A61K31/7048A61K31/713A61K2300/00
Inventor 黄雷靳伟廖晓东吕亚平叶清陈国强
Owner SHANGHAI JIAOTONG UNIV SCHOOL OF MEDICINE
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