CN118340774A - Application of PDI inhibitor CCF642 in preparation of lung adenocarcinoma treatment drug - Google Patents
Application of PDI inhibitor CCF642 in preparation of lung adenocarcinoma treatment drug Download PDFInfo
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- CN118340774A CN118340774A CN202410474256.XA CN202410474256A CN118340774A CN 118340774 A CN118340774 A CN 118340774A CN 202410474256 A CN202410474256 A CN 202410474256A CN 118340774 A CN118340774 A CN 118340774A
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- Prior art keywords
- ccf642
- lung adenocarcinoma
- mice
- application
- pdx
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- SPYIETQLOVDJCF-XYOKQWHBSA-N (5e)-3-(4-methoxyphenyl)-5-[(5-nitrothiophen-2-yl)methylidene]-2-sulfanylidene-1,3-thiazolidin-4-one Chemical compound C1=CC(OC)=CC=C1N(C(=S)S\1)C(=O)C/1=C\C1=CC=C([N+]([O-])=O)S1 SPYIETQLOVDJCF-XYOKQWHBSA-N 0.000 title claims abstract description 38
- 208000010507 Adenocarcinoma of Lung Diseases 0.000 title claims abstract description 17
- 201000005249 lung adenocarcinoma Diseases 0.000 title claims abstract description 17
- 239000003814 drug Substances 0.000 title claims abstract description 14
- 239000003112 inhibitor Substances 0.000 title claims abstract description 9
- 229940079593 drug Drugs 0.000 title description 7
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- 206010028980 Neoplasm Diseases 0.000 abstract description 31
- 241000699670 Mus sp. Species 0.000 abstract description 10
- 230000000694 effects Effects 0.000 abstract description 10
- 230000012010 growth Effects 0.000 abstract description 7
- 206010058467 Lung neoplasm malignant Diseases 0.000 abstract description 4
- 201000005202 lung cancer Diseases 0.000 abstract description 4
- 208000020816 lung neoplasm Diseases 0.000 abstract description 4
- 208000009956 adenocarcinoma Diseases 0.000 abstract description 3
- 238000001727 in vivo Methods 0.000 abstract description 3
- 230000005764 inhibitory process Effects 0.000 abstract description 3
- 230000002035 prolonged effect Effects 0.000 abstract description 3
- 230000004083 survival effect Effects 0.000 abstract description 3
- 230000004614 tumor growth Effects 0.000 abstract description 3
- 210000004027 cell Anatomy 0.000 description 12
- 230000003442 weekly effect Effects 0.000 description 10
- 102000006010 Protein Disulfide-Isomerase Human genes 0.000 description 8
- 108020003519 protein disulfide isomerase Proteins 0.000 description 8
- 238000011740 C57BL/6 mouse Methods 0.000 description 7
- 210000002472 endoplasmic reticulum Anatomy 0.000 description 5
- 238000011725 BALB/c mouse Methods 0.000 description 4
- 238000000692 Student's t-test Methods 0.000 description 4
- 238000010253 intravenous injection Methods 0.000 description 4
- 238000007619 statistical method Methods 0.000 description 4
- 238000012353 t test Methods 0.000 description 4
- 238000007492 two-way ANOVA Methods 0.000 description 4
- 238000011729 BALB/c nude mouse Methods 0.000 description 2
- 210000000683 abdominal cavity Anatomy 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000002513 implantation Methods 0.000 description 2
- 238000011081 inoculation Methods 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 206010009944 Colon cancer Diseases 0.000 description 1
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 1
- 108010006519 Molecular Chaperones Proteins 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 206010061309 Neoplasm progression Diseases 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229960002725 isoflurane Drugs 0.000 description 1
- 108010082117 matrigel Proteins 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000005751 tumor progression Effects 0.000 description 1
Abstract
The invention discloses an application of a PDI inhibitor CCF642 in preparing a medicine for treating lung adenocarcinoma. Experiments prove that CCF642 has an inhibition effect on the growth of xenograft lung cancer cell line (LLC) cells, and simultaneously can reduce the size and weight of tumors; in the established tumor xenograft (PDX) model of the adenocarcinoma patient, the in-vivo curative effect of the CCF642 is quite remarkable; treatment with CCF642 reduced tumor growth and significantly prolonged survival of mice. It can be seen that CCF642 may be useful in treating lung adenocarcinoma.
Description
Technical Field
The invention relates to the technical field of biological medicines, in particular to application of a PDI inhibitor CCF642 in preparation of a medicine for treating lung adenocarcinoma.
Background
There is growing evidence that endoplasmic reticulum stress plays an important role in the progression of a variety of tumors, such as colon cancer, hepatocellular carcinoma, and glioma. Thus, it is speculated that an imbalance in proper folding of endoplasmic reticulum proteins may affect tumor progression from AIS to IAC and may be a potential therapeutic target.
Protein Disulfide Isomerase (PDI) is a disulfide chaperone that regulates the endoplasmic reticulum, which is induced upon endoplasmic reticulum stress, and is necessary for normal folding of proteins in the ER. Inhibition of PDI activity results in increased endoplasmic reticulum stress, exceeding the reparative capacity of cancer cells.
So far, no report on the application of the PDI inhibitor CCF642 to the treatment of lung adenocarcinoma is yet seen at home and abroad.
Disclosure of Invention
The invention aims at overcoming the defects in the prior art and provides application of a PDI inhibitor CCF642 in preparing medicaments for treating lung adenocarcinoma.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
Provides the application of the PDI inhibitor CCF642 in preparing medicaments for treating lung adenocarcinoma.
The structural formula of the inhibitor CCF642 is shown below:
further, the medicine for treating lung adenocarcinoma also comprises a pharmaceutically acceptable carrier and auxiliary materials.
Compared with the prior art, the invention has the following technical effects:
experiments prove that CCF642 has an inhibition effect on the growth of xenograft lung cancer cell line (LLC) cells, and simultaneously can reduce the size and weight of tumors; in the established tumor xenograft (PDX) model of the adenocarcinoma patient, the in-vivo curative effect of the CCF642 is quite remarkable; treatment with CCF642 reduced tumor growth and significantly prolonged survival of mice. It can be seen that CCF642 may be useful in treating lung adenocarcinoma.
Drawings
FIG. 1 shows the growth curves (mean.+ -. SEM) of tumors formed by C57BL/6 mice untreated or treated with CCF642 (10 mg/kg, i.p., twice weekly) allograft WT LLC cells, counted using two-way anova.
FIG. 2 shows the effect of CCF642 on tumor weight formed by C57BL/6 mouse WT LLC cells untreated or CCF642 (10 mg/kg, i.p., twice weekly treatment) and statistical analysis of tumor weight at endpoint using double sided t-test.
FIG. 3 shows tumors formed after xenogeneic inoculation of WT LLC cells in C57BL/6 mice either untreated or treated with CCF642 (10 mg/kg, intravenous injection twice weekly).
Fig. 4 shows the growth curves (mean ± SEM) of tumors formed in BALB/c nude mice after treatment with PDX (PDX-P2) from one lung adenocarcinoma patient untreated or CCF642 (10 mg/kg, i.p., twice weekly), n=6 mice per group, counted using two-way anova.
FIG. 5 shows the effect of CCF642 on tumor weight formation by BALB/c mice vaccinated with lung adenocarcinoma patient derived grafts (PDX) (expressed as SSNs (PDX-P2)), and statistical analysis of tumor weight at endpoint was performed using double sided t-test.
FIG. 6 shows tumors formed in BALB/c mice after PDX-P2 implantation either untreated or treated with CCF642 (10 mg/kg, intravenous injection twice weekly).
Detailed Description
The invention is further described below with reference to the drawings and specific examples, which are not intended to be limiting. It should be noted that, without conflict, the embodiments of the present invention and features of the embodiments may be combined with each other.
Example 1
C57BL/6 female mice 6-8 weeks old were divided into two groups (6 each) and treated with drug and CCF642, respectively. 300 ten thousand LLC cells mixed in Matrigel were injected into the abdomen of 6 mice, producing 10-12 xenograft tumors per group. When tumor volumes reached about 60-80mm 3, they were randomly assigned to different treatment groups. The drugs (PBS and CCF 642) are then directly infused into the abdominal cavity, with a total of 100 microliters of drug per treatment. Treatment was performed twice a week for 4 weeks. On the day of administration, tumors were measured with calipers, body weight was recorded, and the drug was directly injected into the abdominal cavity. Mice were sedated with isoflurane prior to measurement and treatment. The injected dose of CCF642 was 10 mg/kg per mouse. Calculation formula of tumor volume (length. Times. Width 2/2).
The results are shown in FIGS. 1-3.
FIG. 1 shows the growth curves (mean.+ -. SEM) of tumors formed by C57BL/6 mice untreated or treated with CCF642 (10 mg/kg, i.p., twice weekly) allograft WT LLC cells, counted using two-way anova.
FIG. 2 shows the effect of CCF642 on tumor weight formed by C57BL/6 mouse WT LLC cells untreated or CCF642 (10 mg/kg, i.p., twice weekly treatment) and statistical analysis of tumor weight at endpoint using double sided t-test.
FIG. 3 shows tumors formed after xenogeneic inoculation of WT LLC cells in C57BL/6 mice either untreated or treated with CCF642 (10 mg/kg, intravenous injection twice weekly).
It can be seen that CCF642 has an inhibitory effect on the growth of xenograft lung cancer cell line (LLC) cells while reducing tumor size and weight
Example 2
Culture of lung cancer patient derived tumor xenografts (PDX). Mice were subcutaneously implanted with tumor grafts (PDX) derived from lung adenocarcinoma patients. When the average tumor volume reached 60-80mm 3, mice were randomized into two groups and were dosed with PBS or CCF642, respectively, in the same manner as in example 1.
The results are shown in FIGS. 4-6.
Fig. 4 shows the growth curves (mean ± SEM) of tumors formed in BALB/c nude mice after treatment with PDX (PDX-P2) from one lung adenocarcinoma patient untreated or CCF642 (10 mg/kg, i.p., twice weekly), n=6 mice per group, counted using two-way anova.
FIG. 5 shows the effect of CCF642 on tumor weight formation by BALB/c mice vaccinated with lung adenocarcinoma patient derived grafts (PDX) (expressed as SSNs (PDX-P2)), and statistical analysis of tumor weight at endpoint was performed using double sided t-test.
FIG. 6 shows tumors formed in BALB/c mice after PDX-P2 implantation either untreated or treated with CCF642 (10 mg/kg, intravenous injection twice weekly).
It can be seen that in vivo efficacy of CCF642 is also very significant in established tumor xenograft (PDX) models of adenocarcinoma patients; treatment with CCF642 reduced tumor growth and significantly prolonged survival of mice.
The foregoing is merely illustrative of the preferred embodiments of the present invention and is not intended to limit the embodiments and scope of the present invention, and it should be appreciated by those skilled in the art that equivalent substitutions and obvious variations may be made using the teachings and illustrations of the present invention, and that such variations are intended to be included within the scope of the present invention.
Claims (2)
- Application of PDI inhibitor CCF642 in preparing medicaments for treating lung adenocarcinoma.
- 2. The use according to claim 1, wherein the medicament for treating lung adenocarcinoma further comprises a pharmaceutically acceptable carrier and an auxiliary material.
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN118340774A true CN118340774A (en) | 2024-07-16 |
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