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Application of acetyltanshinone IIA in preparation of medicine for treating lung cancer and medicine for treating lung cancer

A technology of acetyl salvia miltiorrhiza and medicine, applied in the field of medicines for the treatment of lung cancer, can solve the problems of temporary, EGFRTKIs resistance, incomplete drug response, etc.

Pending Publication Date: 2022-04-22
UNIVERSITY OF MACAU
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to primary or acquired resistance to EGFR TKIs, the response to these drugs is often incomplete and transient, which has become a complex clinical problem in the course of NSCLC treatment
[0003] Various mechanisms can lead to resistance to EGFR TKIs, study suggests

Method used

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  • Application of acetyltanshinone IIA in preparation of medicine for treating lung cancer and medicine for treating lung cancer
  • Application of acetyltanshinone IIA in preparation of medicine for treating lung cancer and medicine for treating lung cancer
  • Application of acetyltanshinone IIA in preparation of medicine for treating lung cancer and medicine for treating lung cancer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0089] ATA potently inhibits the growth of NSCLC cells with primary or acquired resistance to EGFR TKIs

[0090] Four drug-resistant cell lines were selected, among which A549 and H358 cells had primary resistance to EGFR TKIs (such as Erlotinib, Afatinib, and Osimertinib) due to activating mutations of wild-type EGFR (wt-EGFR) and KRAS. H1975 cells had two mutations in EGFR (L858R and T790M), the second mutation making these cells resistant to erlotinib. H1650 cells had an EGFR-activating mutation (A746-A750 deletion) and a PTEN-deleting mutation. Due to the loss of PTEN, these cells developed resistance to three anti-EGFR drugs, Erlotinib, Afatinib and Osimertinib (as shown in Table 2).

[0091] Table 2 IC of Erlotinib and ATA in drug-resistant NSCLC cells 50 value

[0092]

[0093]

[0094] WT: wild type.

[0095] Among the three EGFR TKIs, comparing the growth inhibitory effect of ATA with the first-generation EGFR TKI: erlotinib, the MTT results showed that in a...

Embodiment 2

[0103] ATA is more effective than Erlotinib in reducing protein levels of EGFR and MET in drug-resistant NSCLC cells

[0104] To determine why ATA was more effective than Erlotinib in inhibiting the growth of drug-resistant NSCLC cells, this example compared their effects on EGFR and MET protein levels in all cell lines used in this study. The results showed that Erlotinib treatment significantly increased the protein levels of EGFR in A549 and H1650. However, in addition to the EGFR protein levels of A549, ATA strongly reduced the EGFR and MET protein levels in drug-resistant NSCLC cells (eg figure 2 shown in A).

[0105] Further, in order to confirm whether ATA can inhibit the growth of drug-resistant NSCLC by reducing the levels of EGFR and MET, A549, H358, H1975 and H1650 cells were treated with 1 or 2 μM ATA for 48 hours, and the results of Western blot showed that: 1 or 2 μM ATA ATA greatly reduced EGFR protein levels by 60-70% in H358, H1975 and H1650 cells, and 2 μM...

Embodiment 3

[0110] ATA inhibits the growth of drug-resistant NSCLC cells by reducing p70S6K

[0111] To study the effect of ATA on the downstream signaling pathways of EGFR and MET, the results of Western blot showed that ATA treatment did not significantly reduce the levels of p-Akt, Akt, p-mTOR and mTOR in most cell lines, but greatly reduced p70S6K protein and levels of its phosphorylated form. In addition, ATA also significantly reduced the phosphorylation of S6 ribosomal protein (S6RP), which can be phosphorylated by p70S6K; however, ATA did not greatly reduce the level of S6RP protein (eg image 3 shown in A). Confocal immunofluorescent staining also confirmed that ATA treatment decreased the levels of p-S6RP in A549 and H358 cells (eg Figure 10 shown in A).

[0112] Since the phosphorylation of S6RP by p70S6K can induce protein synthesis in ribosomes, an experiment was conducted to determine whether the reduction of p70S6K by ATA would affect the synthesis of new proteins. The ...

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Abstract

The invention discloses application of acetyltanshinone IIA in preparation of a medicine for treating lung cancer and the medicine for treating lung cancer, and belongs to the technical field of medicines. According to the scheme, the application of the acetyltanshinone IIA in treating lung cancer, especially non-small cell lung cancer (NSCLC) is provided, and the small molecule compound acetyltanshinone IIA can be used for resisting primary and acquired drug resistance of NSCLC cells to epidermal growth factor receptors, namely tyrosine kinase inhibitors (EGFR TKIs). The invention further determines the molecular target of the ATA, and clarifies the mechanism of the ATA for inhibiting the growth of drug-resistant NSCLC cells and tumors. The drug containing the acetyltanshinone IIA is expected to be developed into a multi-target anticancer agent for treating TKI drug-resistant NSCLC.

Description

technical field [0001] The invention relates to the technical field of medicines, in particular to the application of acetyltanshinone IIA in the preparation of medicines for treating lung cancer and the medicines for treating lung cancers. Background technique [0002] Among all types of cancer, lung cancer has the highest incidence and mortality rates in the world, with 2.1 million new cases and approximately 1.8 million deaths worldwide in 2018. Non-small cell lung cancer (NSCLC) accounts for 85% of all newly diagnosed lung cancers and is the major histological subtype of the disease. Epidermal growth factor receptor (EGFR) activating mutations are the most common driver mutations and can be targeted for treatment in NSCLC. The development of EGFR-targeted therapies has revolutionized the clinical management of NSCLC. Targeted therapy with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) has improved the prognosis of NSCLC patients. However, due ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/58A61P35/00
CPCA61K31/58A61P35/00
Inventor 罗茜黄斌
Owner UNIVERSITY OF MACAU
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