CN114522154A - Application of enbeiric acid in combination with oxaliplatin for treating microsatellite unstable colorectal cancer - Google Patents
Application of enbeiric acid in combination with oxaliplatin for treating microsatellite unstable colorectal cancer Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/12—Ketones
- A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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Abstract
The invention discloses an application of embellic acid in combination with oxaliplatin for treating microsatellite unstable colorectal cancer, and belongs to the technical field of biological medicines. Enfibric acid is a quinone compound isolated from Japanese ardisia herb, belongs to a natural product class of medicines, and is currently approved by the FDA to enter the preclinical research stage of antitumor treatment. Research results of the invention show that the enberylic acid can obviously increase the sensitivity of microsatellite unstable colorectal cancer to chemotherapeutic drug oxaliplatin. Based on the invention, a new strategy for the combined synergistic treatment of the microsatellite unstable colorectal cancer based on the treatment of the enbesylic acid and the oxaliplatin medicaments is provided for the first time, which is favorable for improving the treatment level of the colorectal cancer chemotherapeutics and increasing the application range of the enbesylic acid in tumor treatment.
Description
Technical Field
The invention relates to application of embelin in combination with oxaliplatin for treating microsatellite unstable colorectal cancer, belonging to the technical field of biological medicines.
Background
Colorectal cancer is one of the most common digestive tract malignancies and is also one of the major cancer causing death in cancer patients. Currently, adjuvant chemotherapy based on tumor staging after surgical resection is one of the most common treatment strategies. For patients with advanced colorectal cancer that are not surgically resectable, treatment regimens include chemotherapy, targeting and immunotherapy. Wherein oxaliplatin-based chemotherapy is a first-line treatment regimen, combined with 5-fluorouracil (5-FU) and calcium folinate (LV) (FOLFOX), has an effective rate of >50% for the treatment of metastatic colorectal cancer, has a median survival time of nearly 2 years, and is predominant in the treatment of patients with advanced colorectal cancer. However, a large proportion of patients receiving chemotherapy inevitably develop resistance, greatly affecting the efficacy of treatment of advanced colorectal cancer.
Microsatellite instability (MSI), which refers to the increase or loss of the number of repeated sequences in the genome due to errors in gene replication, results in a shortening or lengthening of the length of the microsatellite fragment. Colorectal cancer can be classified into 3 categories according to the frequency with which MSI is detected in colorectal cancer: microsatellite high instability (MSI-H), microsatellite low instability (MSI-L) and microsatellite stability (MSS). MSI-H occurs in 15% to 20% of stage II and III CRC patients with better prognosis compared to MSS patients, but MSI-H is present in about 5% of metastatic colorectal patients and has a poorer prognosis. Therefore, there is a need for novel methods to enhance the anti-tumor response of chemotherapy to prolong the survival of advanced colorectal cancer patients.
Disclosure of Invention
The invention provides an application of embelin in combination with oxaliplatin for treating microsatellite unstable colorectal cancer, which is used for enhancing the anti-tumor response of a chemotherapy to prolong the survival time of a patient with advanced colorectal cancer.
The invention is realized by adopting the following technical scheme:
application of embelin in combination with oxaliplatin for treating microsatellite-unstable colorectal cancer.
As a preferred example, the application of enbeiic acid in preparing a medicament for treating microsatellite unstable colorectal cancer.
As a preferable example, the enbesylic acid can increase the sensitivity of microsatellite unstable colorectal cancer to a chemotherapeutic drug oxaliplatin, can inhibit the proliferation of colorectal cancer cells in vitro, can induce the apoptosis of the colorectal cancer cells, and can significantly inhibit the growth of the colorectal cancer in vivo.
As a preferred example, the concentration of the Enfibric acid is 15mg/kg, and the Enfibric acid is injected into abdominal cavity/tail vein; the administration concentration of the oxaliplatin is 5mg/kg, and the oxaliplatin is injected into abdominal cavity/tail vein.
As a preferable example, the embelin is a natural product isolated from Japanese ardisia herb, and can induce apoptosis of colorectal cancer cells and inhibit colorectal cancer growth as an inhibitor of X-linked apoptosis protein.
The invention has the beneficial effects that: embelin is a quinone compound separated from Japanese ardisia herb, belongs to a natural product class of medicines, and is approved by FDA to enter the preclinical research stage of antitumor therapy at present; research results of the invention show that the enbesylic acid can obviously increase the sensitivity of microsatellite unstable colorectal cancer to chemotherapeutic drug oxaliplatin, and based on the enbesylic acid and oxaliplatin, a new strategy for microsatellite unstable colorectal cancer combined synergistic treatment based on drug treatment of the enbesylic acid and the oxaliplatin is provided for the first time, so that the improvement of the colorectal cancer chemical drug treatment level is facilitated, and the application range of the enbesylic acid in tumor treatment is increased.
Drawings
FIG. 1 is a drug dose-response curve of the present invention;
FIG. 2 is a schematic illustration of the evaluation of the synergistic effect of the combination therapy of the present invention;
FIG. 3 is a schematic illustration of the effect of embelin on apoptosis;
FIG. 4 is a schematic diagram showing the effect of embellic acid on the growth of the colon cancer cell strains RKO-OXPT and SW1463 in vivo.
Detailed Description
In order to make the technical means, the original characteristics, the achieved purpose and the efficacy of the invention easy to understand, the invention is further described with reference to the specific drawings.
Experiments show that the enbeiic acid has the effect on treating microsatellite unstable colorectal cancer by oxaliplatin, and the specific operation steps of the experiments are as follows:
1. cell viability assay
Cell viability was measured by the CCK8 method, and cells were seeded in 96-well plates (103 cells, 100. mu.l per well) and processed according to the grouping. After 72 hours, 10. mu.l of CCK8 reagent was added to each well, and after incubation at 37 ℃ for 2 hours, the absorbance at 450 nm was measured with a spectrophotometer. The synergistic effect of the combination treatment was assessed by isoline photography of Chou and Talalay11 using the Calcusyn software program. CI > 1 indicates antagonism and CI <1 indicates synergy.
2. Apoptosis detection
Annexin V-FITC apoptosis detection kit (BD Pharmingen) was used to detect the expression of Annexin V and the uptake of Propidium Iodide (PI) on the cell surface by flow cytometry. Cells were collected, washed twice with ice-cold PBS and suspended in 100 μ l binding buffer. Cells were stained with 3 μ l Annexin V-FITC and 5 μ l Propidium Iodide (PI) for 15 minutes at room temperature in the dark. Apoptosis was analyzed by flow cytometry using the FACS Calibur system.
3. Subcutaneous tumor formation experiment of nude mice
Preparing the stably-growing colorectal cancer cells into serum-free suspension, taking a male nude mouse with age of 4-6 weeks, and injecting tumor cells into the right lower abdomen of the mouse respectively. Oxaliplatin and enbernic acid were administered by tail vein/intraperitoneal injection. The administration concentration of the enbenoic acid is 15mg/kg, and the administration concentration of the oxaliplatin is 5 mg/kg. Tumor diameter was measured with a vernier caliper every 2 days and observed continuously for 2 weeks.
The present invention will be described in detail below with reference to specific examples.
Example 1
The effect of embelin on the growth of the colon cancer cell lines RKO, HCT116 and HT 29.
(1) Subject: micro-satellite unstable (MSI-H) colorectal cancer cell lines RKO and HCT116, and micro-satellite stable (MSS) colorectal cancer cell line HT 29.
(2) A detection step: cells were seeded in 96-well plates (103 cells, 100 μ l per well) and treated with oxaliplatin, enbesylic acid, oxaliplatin + enbesylic acid, respectively. The dosing concentration of the embonic acid and the oxaliplatin is 0, 0.25, 0.5, 1, 3, 6, 13, 25, 50 and 100 mu M. After 72 hours, 10. mu.l of CCK8 reagent was added to each well, and after incubation at 37 ℃ for 2 hours, the absorbance at 450 nm was measured with a spectrophotometer. Drug dose-response curves were plotted (fig. 1) and the synergistic effect of the combination treatment was assessed by isoline photography of Chou and Talalay11 using the Calcusyn software program (fig. 2). CI > 1 indicates antagonism and CI <1 indicates synergy.
(3) And (3) detection results: treatment with embonic acid in combination with oxaliplatin had a clear synergistic effect on RKO and HCT116, whereas treatment with embonic acid in combination with oxaliplatin had no clear synergistic effect on HT29 (FIG. 2).
Example 2
The effect of embelin on apoptosis of the colon cancer cell strains RKO, HCT116 and HT 29.
(1) Subject: micro-satellite unstable (MSI-H) colorectal cancer cell lines RKO and HCT116, and micro-satellite stable (MSS) colorectal cancer cell line HT 29.
(2) A detection step: cells were seeded in 12-well plates (104 cells, 500 μ l per well) and treated with oxaliplatin, enbesylic acid, oxaliplatin + enbesylic acid, respectively. The administration concentration of enbenoic acid is 20 μ M and the administration concentration of oxaliplatin is 10 μ M. After 24 hours, cells were harvested, washed twice with ice-cold PBS and suspended in 100 μ l binding buffer. Cells were stained with 3 μ l Annexin V-FITC and 5 μ l Propidium Iodide (PI) for 15 minutes at room temperature in the dark. Apoptosis was analyzed by flow cytometry using the FACS Calibur system.
(3) And (3) detection results: embonic acid in combination with oxaliplatin treatment significantly increased apoptosis of RKO and HCT116 compared to monotherapy, and embonic acid in combination with oxaliplatin treatment did not significantly increase apoptosis of HT29 (FIG. 3).
Example 3
The effect of embelin on the growth of the colon cancer cell strains RKO and SW1463 in vivo.
(1) Subject: the oxaliplatin-resistant strain of the in vitro induced microsatellite unstable (MSI-H) colorectal cancer cell strain RKO has certain resistance to oxaliplatin treatment. A micro-satellite stabilized (MSS) colorectal cancer cell line SW 1463.
(2) A detection step: preparing the cells into serum-free suspension, taking a 4-6-week-old male nude mouse, and injecting tumor cells into the right lower abdomen of the mouse respectively. The treatment is divided into 4 groups, namely a control group, an oxaliplatin group, an enfibric acid group and an oxaliplatin + enfibric acid group. The administration concentration of the enbenoic acid is 15mg/kg, and the administration concentration of the oxaliplatin is 5 mg/kg. Oxaliplatin and enbeiic acid were administered by tail vein/intraperitoneal injection, on days 5, 7, 9, 12 after cell injection, respectively, and tumor body diameter was measured with a vernier caliper for 2 weeks.
(3) And (3) detection results: in the microsatellite stabilized (MSS) colorectal cancer cell line SW1463, the growth of SW1463 was not significantly inhibited by the combination of embonic acid and oxaliplatin compared to monotherapy. In the microsatellite unstable (MSI-H) colorectal cancer cell line RKO, embonic acid in combination with oxaliplatin treatment significantly inhibited the growth of RKO resistant strains compared to monotherapy (fig. 4).
In conclusion, Embelin is a natural product isolated from Japanese Ardisia (Ardisia) herb, and has been spotlighted in the field of cancer research due to its pharmacological properties and non-toxic properties. As an inhibitor of X-linked apoptosis protein inhibitor (XIAP), Embelin is combined with BIR3 domain shared by IAP family, and can inhibit the functions of NAIP, cIAP1, cIAP2 and XIAP, thereby inducing apoptosis of various cancer cells and achieving the purpose of inhibiting growth, proliferation and migration of the cancer cells.
The family of apoptosis protein Inhibitors (IAPs) contains a group of evolutionarily conserved apoptosis inhibitors, and inhibition of apoptosis is one of the important mechanisms of tumor cells to resist the killing action of chemotherapeutic drugs such as oxaliplatin. The enfibric acid can recover the apoptosis of tumor cells induced by oxaliplatin by inhibiting the function of IAP, thereby achieving the effect of increasing the sensitivity of intestinal cancer cells to oxaliplatin. In microsatellite unstable colorectal cancers, there is an overactivated cIAP2 molecular signaling pathway. The enfibric acid restores the apoptosis induced by the oxaliplatin by inhibiting the anti-apoptosis function of the cIAP2, so the combination of the enfibric acid and the oxaliplatin has good effect on treating the microsatellite unstable colorectal cancer
The foregoing shows and describes the general principles and broad features of the present invention and advantages thereof. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, and that various changes and modifications may be made without departing from the spirit and scope of the invention as defined in the appended claims. The scope of the invention is defined by the appended claims and equivalents thereof.
Claims (5)
1. Application of embelin in combination with oxaliplatin for treating microsatellite-unstable colorectal cancer.
2. Use according to claim 1, characterized in that: application of embelin in preparation of medicine for treating microsatellite unstable colorectal cancer.
3. Use according to claim 1, characterized in that: the enfibric acid can increase the sensitivity of microsatellite unstable colorectal cancer to a chemotherapeutic drug oxaliplatin, can inhibit the proliferation of colorectal cancer cells in vitro, induces the apoptosis of the colorectal cancer cells, and obviously inhibits the growth of the colorectal cancer in vivo.
4. Use according to claim 1, characterized in that: the administration concentration of the embelin is 15mg/kg, and the enbenoic acid is injected into abdominal cavity/tail vein; the administration concentration of the oxaliplatin is 5mg/kg, and the oxaliplatin is injected into abdominal cavity/tail vein.
5. Use according to claim 1, characterized in that: the embelin is a natural product isolated from Japanese ardisia japonica, and can be used as inhibitor of X-linked apoptosis protein inhibitor for inducing apoptosis of colorectal cancer cells and inhibiting growth of colorectal cancer.
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|---|---|---|---|
| CN202210173954.7A CN114522154A (en) | 2022-02-24 | 2022-02-24 | Application of enbeiric acid in combination with oxaliplatin for treating microsatellite unstable colorectal cancer |
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| CN202210173954.7A CN114522154A (en) | 2022-02-24 | 2022-02-24 | Application of enbeiric acid in combination with oxaliplatin for treating microsatellite unstable colorectal cancer |
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2022
- 2022-02-24 CN CN202210173954.7A patent/CN114522154A/en not_active Withdrawn
Non-Patent Citations (1)
| Title |
|---|
| 赵剑波等: "奥沙利铂对结肠癌细胞XIAP表达及凋亡的影响", 齐齐哈尔医学院学报, vol. 29, no. 8, pages 893 * |
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