CN113876753A - Pharmaceutical application of recombinant human galectin 1 inhibitor - Google Patents

Pharmaceutical application of recombinant human galectin 1 inhibitor Download PDF

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CN113876753A
CN113876753A CN202111221452.9A CN202111221452A CN113876753A CN 113876753 A CN113876753 A CN 113876753A CN 202111221452 A CN202111221452 A CN 202111221452A CN 113876753 A CN113876753 A CN 113876753A
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albumin
bound paclitaxel
inhibitor
lgals1
gastric cancer
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崔越宏
刘天舒
朱梦璇
张鹏飞
李倩
于珊
王四维
彭轲
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Zhongshan Hospital Fudan University
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
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    • A—HUMAN NECESSITIES
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    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
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Abstract

The invention provides application of an LGALS1 inhibitor in preparing an anti-albumin-bound paclitaxel drug resistance medicament and an anti-tumor medicament. Experiments prove that the LGALS1 inhibitor OTX008 has the drug resistance effect of resisting albumin-bound paclitaxel, and the drug and the albumin-bound paclitaxel have the synergistic anti-tumor effect. Has great clinical significance for further developing related therapeutic drugs.

Description

Pharmaceutical application of recombinant human galectin 1 inhibitor
Technical Field
The invention relates to the technical field of medicines, in particular to a pharmaceutical application of a recombinant human galectin 1 inhibitor.
Background
Gastric Cancer (GC) is one of the most common malignant tumors in the world, more than 100 million new cases are added in the world in 2020, resulting in about 76.9 million deaths of patients, wherein more than 60% of cases occur in east Asia population, and the incidence and mortality of Gastric cancer in China are in the world front. Because gastric cancer is hidden and gastroscope screening is not popularized yet, about 80 percent of Chinese gastric cancer patients have distant metastasis when diagnosed, cannot be subjected to radical surgery, and have a five-year survival rate of less than 20 percent after chemotherapy and targeted therapy. Chemotherapy resistance is an important cause of poor patient prognosis.
Paclitaxel is a diterpenoid compound, and mainly inhibits depolymerization of tubulin, prevents mitosis, makes cells stay in G2/M phase, finally induces apoptosis, and plays an anti-tumor role. Because the paclitaxel is not dissolved in water, solvents such as ethanol and castor oil are required to be used for dissolving, side reactions such as allergy, peripheral neuropathy and the like are easily caused, and the clinical application of the paclitaxel is greatly limited. Albumin-bound paclitaxel (Nab-PTX) is prepared by combining hydrophobic paclitaxel with albumin by using nanotechnology, and is a solvent-free paclitaxel formulation, which can improve the curative effect of paclitaxel and simultaneously reduce the toxicity. The anti-tumor effect of the albumin-bound paclitaxel has been proved in various solid tumors, and the albumin-bound paclitaxel is approved to be applied to the first-line treatment of breast cancer, non-small cell lung cancer and esophageal cancer and the second-line treatment of gastric cancer at present. However, clinically, the response rate of albumin-bound paclitaxel is only 35%, and therefore, exploring the drug resistance mechanism of albumin-bound paclitaxel is crucial to improving the prognosis of gastric cancer patients.
Recombinant human galectin 1(LGALS1) is a member of the galectin family, and this class of proteins binds to galactoside permeases, regulates cell-cell and cell-matrix interactions, and induces apoptosis, proliferation and differentiation. There is no report of LGALS1 inhibitors overcoming resistance to albumin-bound paclitaxel.
Therefore, there is a need to obtain an albumin-bound paclitaxel drug-resistant marker of gastric cancer clinically, and develop a drug that can overcome the drug resistance of albumin-bound paclitaxel and further improve the therapeutic effect of gastric cancer patients.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention is realized by the following technical scheme:
the invention provides the application of an LGALS1 inhibitor in preparing an anti-albumin-bound paclitaxel drug resistance medicament;
the second aspect of the invention provides the use of an LGALS1 inhibitor in the preparation of an anti-tumor medicament;
further, the anti-tumor drug has the effect of treating gastric cancer;
furthermore, the anti-tumor medicine also contains albumin-bound paclitaxel;
further, the LGALS1 inhibitor is OTX008, and the structure of the LGALS1 inhibitor is shown in a formula I:
Figure BDA0003312782990000021
drawings
FIG. 1: FIG. 1A is a heat map of genes differentially expressed in gastric cancer and paracarcinoma tissues of patients receiving albumin-bound paclitaxel therapy; FIG. 1B is a heat map of differentially expressed genes in gastric cancer tissue from patients who are sensitive to albumin-bound paclitaxel treatment versus those who are not; fig. 1C is a graph of ZFP64 protein levels in gastric cancer tissue from patients sensitive to albumin-bound paclitaxel treatment versus non-sensitive patients;
FIG. 2: FIG. 2A shows that two shRNAs knock down ZFP64 respectively, and the influence of the two shRNAs on the sensitivity of gastric cancer cell albumin-bound paclitaxel is detected; fig. 2B shows overexpression of ZFP64 in gastric cancer MGC803 cells, tested for sensitivity to albumin-bound paclitaxel; FIG. 2C shows the overexpression of ZFP64 in gastric carcinoma HGC27 cells, tested for sensitivity to albumin-bound paclitaxel;
FIG. 3 is a graph of the change in albumin-bound paclitaxel-induced apoptosis by gastric cancer cell lines following knockdown or overexpression of ZFP 64;
FIG. 4: fig. 4A is a graph of the knockdown of LGALS1, ZFP64 and LGALS1 protein expression in ZFP64 overexpressing or control cells, respectively; FIG. 4B is a graph showing the detection of apoptosis of the above groups of cells in the presence of albumin-bound paclitaxel; FIG. 4C is a graph showing the detection of the colony formation of the above groups of cells under the treatment of the albumin-bound paclitaxel;
FIG. 5: FIG. 5A is a graph of the effect of the LGALS1 inhibitor OTX008 in combination with albumin-bound paclitaxel on the proliferation of gastric cancer cell lines; FIG. 5B shows the inhibitory effect of the LGALS1 inhibitor OTX008 in combination with albumin-bound paclitaxel on subcutaneous tumors in mice; FIG. 5C is a graph of tumor volume measurements for the above groups of mice; FIG. 5D is a graph showing tumor weight measurements in the above groups of mice.
Advantageous effects
The invention is proved by experiments that:
(1) experiments on a molecular level prove that the ZFP64 is highly expressed in gastric cancer tissues, particularly gastric cancer tissues insensitive to albumin-bound paclitaxel treatment, and the high expression of the gene causes the transformation of dry phenotype of gastric cancer cells, so that the capacities of proliferation and invasion of the gastric cancer cells and the like are enhanced, and the sensitivity to chemotherapeutic drugs is reduced;
(2) according to the invention, by exploring the molecular mechanism of ZFP64, experiments prove that LGALS1 is a target gene at the downstream of ZFP64 and is a key gene causing the phenotypic change of gastric cancer cells;
(3) experiments further prove that the LGALS1 inhibitor OTX008 has the drug resistance effect of resisting the albumin-bound paclitaxel, the OTX008 can enhance the anti-tumor effect of the albumin-bound paclitaxel, and the drug and the albumin-bound paclitaxel have the synergistic anti-tumor effect.
Detailed Description
The present invention will be described in further detail with reference to the accompanying drawings and specific embodiments.
OTX008, a new generation of LGALS1 selective small molecule inhibitor,has the characteristics of high specificity, low toxicity and the like, is proved to be capable of specifically inhibiting the expression of Galectin-1 protein, and has the functions of reducing the migration and invasion of tumor cells, the formation of tumor neovascularization and the like. The chemical formula is as follows: 2,2',2 ", 2'" - [ pentacyclic [19,3,1,13,7,19,13,115,19]Octacosyl-1 (25),3,5,7(28),9,11,13(27),15,17,19(26), 21, 23-dodecene-25, 26,27, 28-tetraalkyltetraoxytetra [ N- [ 2-dimethylamino) ethyl]Acetamide (i.e. 2,2',2 ", 2'" - [ pentacyclo [19,3,1,13,7,19,13,115, 19)]octacosa-1(25),3,5,7(28),9, 11,13(27),15,17 19(26),21,23-dodecaene-25,26,27, 28-tetraylterakis(oxy)tetrakis[N-[2-dimethylamino)ethyl]-acetamides); molecular weight of 937.2 and molecular formula of C52H72N8O8The CAS registry number is: 286936-40-1, the structure is shown in formula I:
Figure BDA0003312782990000041
in the following examples, reference to gastric cancer tissue and tissues adjacent to it was provided by the oncology department of the subsidiary Zhongshan Hospital, university of Compound Dane, and approved by the ethical Committee of hospitals. The nude mouse is provided by Beijing Witonglihua laboratory animal technology GmbH; OTX008 was purchased from MCE, ZFP64 and GAPDH antibodies were purchased from Abcam; gastric cancer AGS, HGC27, and MGC803 cells were purchased from shanghai medcinal hospital cell bank; the rest of the conventional reagents are commercially available.
Example 1ZFP64 Gene expression affects the sensitivity of gastric cancer cells to albumin-bound paclitaxel
(1) Transcriptomic sequencing was performed on 2 cases of albumin-bound paclitaxel-resistant and 2 cases of albumin-bound paclitaxel-sensitive gastric cancer tissues and their paracarcinoma tissues, and differential expression gene analysis was performed using the DESeq 2R package, and as a result, the mRNA level of the ZFP64 gene was higher in drug-resistant gastric cancer tissues, as shown in fig. 1A and 1B.
(2) Respectively grinding 2 samples of the drug-resistant gastric cancer tissue sensitive to albumin-bound paclitaxel and 2 samples of the gastric cancer tissue sensitive to albumin-bound paclitaxel, extracting protein samples, and performing protein gel separation by SDS-PAGE electrophoresis, wherein the voltage of a concentrated gel is 80V, and the voltage of a separation gel is 120V. And transferring the protein gel onto a PVDF membrane subjected to methanol pretreatment under the constant current of 300mA for 90 min. PVDF membrane in 5% skim milk blocking for 1 hours, then in the corresponding primary antibody 4 degrees C were incubated overnight. After 3 washes with 1 × TBST, incubation with the corresponding secondary antibody for 1 hour was performed and finally visualized by a gel imaging system. The results are shown in fig. 1C, where the protein expression level of ZFP64 is higher in drug-resistant gastric cancer tissues than in sensitive gastric cancer tissues.
Example 2 drug sensitivity assay for Albumin-bound paclitaxel
(1) Control unloaded and ZFP64 plasmids were overexpressed in HGC27 and MGC803 cells, respectively, and cell viability was examined at different time points by the method of CCK8 using 5nM albumin-bound paclitaxel for 12h, 24h, 48h, 72 h. The results are shown in fig. 2A, where overexpression of ZFP64 protein promotes resistance of gastric cancer cells to albumin-bound paclitaxel.
(2) The expression level of ZFP64 in an AGS cell strain is knocked down by shRNA lentivirus (5'-CTATCCAGGTTGCCAGTTCAA-3'), AGS cells and control cells with stably knocked-down ZFP64 are inoculated into a 96-well plate according to 1500 holes, 5nM albumin-bound paclitaxel is used for treating 12h, 24h, 48h and 72h, and the cell activity at different time points is detected by a CCK8 method. The results are shown in fig. 2B, where knock-down of ZFP64 increased the sensitivity of AGS cells to albumin-bound paclitaxel.
Example 3 apoptosis assay after treatment with Albumin-bound paclitaxel
(1) Inoculating the AGS cells and the control cells of stably knocked-down ZFP64 in a 6-well plate, treating for 48h by using 15nM albumin-bound paclitaxel or PBS, detecting the apoptosis conditions before and after treatment by using a flow cytometer, and analyzing data by using FlowJo software;
(2) HGC27 and MGC803 cells stably overexpressing ZFP64 and control cells thereof were seeded in 6-well plates and treated with 5nM albumin-bound paclitaxel or PBS for 48h, and apoptosis before and after treatment was detected by flow cytometry and data analysis was performed by FlowJo software.
Analysis of the results of (1) and (2) showed that ZFP64 prevented albumin-bound paclitaxel-induced apoptosis, as shown in fig. 3.
Example 4ZFP64 Induction of Albumin-bound paclitaxel resistance dependent on LGALS1
The important role of ZFP64 protein in the drug resistance of gastric cancer albumin-bound paclitaxel is proved in the forward and reverse directions by knocking down and over expressing ZFP64, and considering that ZFP64 is a transcription factor, the ZFP64 is presumed to play the role of promoting cancer by regulating and controlling the transcription of a downstream target gene LGALS 1.
(1) Transfection of the LGALS 1-knocked-down lentivirus shLGALS1 (5'-GCAAAGACAGCAACAACCUTT-3') and control lentiviruses in HGC27 and MGC803 cells stably overexpressing ZFP64 and their control cells, as shown in fig. 4A;
(2) shLGALS1 and its control lentivirus transfected HGC27, MGC803 cells were seeded in 6-well plates and treated with 5nM albumin-bound paclitaxel for 48h, flow cytometrically detected apoptosis and data analyzed using FlowJo software. As shown in fig. 4B, knockdown of LGALS1 reversed the resistance of ZFP64 overexpressing cells to albumin-bound paclitaxel-induced apoptosis;
(3) shLGALS1 and its control lentivirus transfected HGC27, MGC803 cells were treated with 5nM albumin-bound paclitaxel for 24h, then inoculated into 6 well plates at 1000 per well, 14 days later culture fluid was discarded, 200. mu.l of 4% paraformaldehyde was added to fix the cells, then fluid was discarded, 0.1% crystal violet stain was used to stain the cells for 30min, finally unbound crystal violet was washed off with PBS, stained cells were photographed and counted, the results are shown in FIG. 4C, and the knock-down of LGALS1 reversed the resistance of ZFP64 overexpressing cells to the growth inhibition induced by albumin-bound paclitaxel.
Example 5 combination therapy of LGALS1 inhibitor OTX008 and Albumin-bound paclitaxel against subcutaneous tumors in mice
(1) HGC27, MGC803 and AGS cells are inoculated to a 96-well plate and respectively treated with albumin-bound paclitaxel, an LGALS1 inhibitor OTX008 and a combination of the two, and CCK8 detection is carried out after 48 hours. The results are shown in figure 5A, where the combination of LGALS1 inhibitor and albumin-bound paclitaxel had a more significant inhibitory effect on gastric cancer cells than either drug alone.
(2) For in vivo experiments in mice, 1X 106The individual ZFP64 stably over-expressed HGC27 cells were inoculated to the axilla of nude mice subcutaneously, and 20 mice with approximate tumor size were selected for drug combination treatment about 20 days. The doses used were albumin-bound paclitaxel (10mg/kg), the LGALS1 inhibitor OTX008(5mg/kg), and administered 2 times a week via the tail vein. Tumor size and weight of mice were recorded 21 days after dosing. The results are shown in figures 5B, 5C, 5D, where the combination of albumin-bound paclitaxel and LGALS1 inhibitor had a more significant inhibitory effect on subcutaneous albumin-bound paclitaxel-insensitive tumors in mice than either drug alone.
The foregoing detailed description of the preferred embodiments of the invention has been presented. It should be understood that numerous modifications and variations could be devised by those skilled in the art in light of the present teachings without departing from the inventive concepts. Therefore, the technical solutions available to those skilled in the art through logic analysis, reasoning and limited experiments based on the prior art according to the concept of the present invention should be within the scope of protection defined by the claims.
SEQUENCE LISTING
<110> Zhongshan Hospital affiliated to Fudan university
<120> pharmaceutical use of recombinant human galectin 1 inhibitor
<130> 2
<160> 2
<170> PatentIn version 3.3
<210> 1
<211> 21
<212> DNA
<213> Artificial sequence (artificial sequence)
<400> 1
ctatccaggt tgccagttca a 21
<210> 2
<211> 21
<212> DNA
<213> Artificial sequence (artificial sequence)
<400> 2
gcaaagacag caacaaccut t 21

Claims (5)

  1. Use of an LGALS1 inhibitor for the preparation of a medicament against resistance to albumin-bound paclitaxel.
  2. Use of an LGALS1 inhibitor in the preparation of an anti-tumor medicament.
  3. 3. The use according to claim 2, wherein the antitumor agent has an effect of treating gastric cancer.
  4. 4. The use according to claim 2, wherein the antitumor drug further comprises albumin-bound paclitaxel.
  5. 5. The use according to any one of claims 1 to 4, wherein the LGALS1 inhibitor is OTX008 having the structure according to formula I:
    Figure FDA0003312782980000011
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012131079A1 (en) * 2011-03-30 2012-10-04 Oncoethix Compounds inhibiting galectin-1 expression, cancer cell proliferation, invasion, and tumorigenesis
US20140121278A1 (en) * 2012-11-01 2014-05-01 Regents Of The University Of Minnesota Anti-tumor agent otx-008 targets human galectin-1
US20170253933A1 (en) * 2014-12-23 2017-09-07 Genentech, Inc. Compositions and methods for treating and diagnosing chemotherapy-resistant cancers

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012131079A1 (en) * 2011-03-30 2012-10-04 Oncoethix Compounds inhibiting galectin-1 expression, cancer cell proliferation, invasion, and tumorigenesis
US20140121278A1 (en) * 2012-11-01 2014-05-01 Regents Of The University Of Minnesota Anti-tumor agent otx-008 targets human galectin-1
US20170253933A1 (en) * 2014-12-23 2017-09-07 Genentech, Inc. Compositions and methods for treating and diagnosing chemotherapy-resistant cancers

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
XIAOLAN YOU等: "Galectin-1 From Cancer-Associated Fibroblasts Promotes the Invasion and Metastasis of Gastric Cancer Through TGF-β1-Induced EpithelialMesenchymal Transition" *
XIAOLAN YOU等: "Galectin-1 promotes vasculogenic mimicry in gastric adenocarcinoma via the Hedgehog/GLI signaling pathway" *
华秋等: "环氧合酶－２和半乳糖凝集素－１与胃癌关系的研究进展" *

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