CN114984027A - Application of saikosaponin A in preparation of medicine for relieving toxic and side effects of EGFR inhibitor - Google Patents
Application of saikosaponin A in preparation of medicine for relieving toxic and side effects of EGFR inhibitor Download PDFInfo
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- CN114984027A CN114984027A CN202210458564.4A CN202210458564A CN114984027A CN 114984027 A CN114984027 A CN 114984027A CN 202210458564 A CN202210458564 A CN 202210458564A CN 114984027 A CN114984027 A CN 114984027A
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- saikosaponin
- lapatinib
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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Abstract
The invention discloses application of saikosaponin A in preparation of a medicine for relieving toxic and side effects of an EGFR inhibitor, and belongs to the field of medicines. The saikosaponin A can obviously improve the toxic side effects of dry skin, desquamation, inflammatory reaction, liver injury and the like caused by EGFR inhibitor medicines. The saikosaponin A is combined with EGFR inhibitor drugs, so that the toxic and side effects of the saikosaponin A are effectively reduced, the safety of the EGFR inhibitor drugs is improved, and the clinical application of the saikosaponin A is expanded. The saikosaponin A has low dosage, high safety and moderate price, can be prepared into proper dosage forms according to requirements, and has high clinical feasibility.
Description
Technical Field
The invention relates to the field of medicines, in particular to application of saikosaponin A in treatment of organ toxicity such as skin toxicity and liver toxicity induced by epidermal growth factor receptor inhibitors, such as lapatinib, so as to relieve toxic side effects caused by lapatinib.
Background
Lapatinib (Lapatinib, Tilisa) is a potent ATP competitive small molecule tyrosine kinase inhibitor, and can effectively inhibit the tyrosine kinase activity of human epidermal growth factor receptor-1 (ErbB1) and human epidermal growth factor receptor-2 (ErbB 2). Lapatinib is a breast cancer targeted therapeutic drug, the action mechanism of the Lapatinib is that the ATP sites of EGFR (ErbB-1) and HER2(ErbB-2) in cells are inhibited to prevent the phosphorylation and activation of tumor cells, and the down-regulation signals are blocked by homo-dimers and hetero-dimers of EGFR (ErbB-1) and HER2 (ErbB-2).
Lapatinib is currently approved for the treatment of patients with advanced or metastatic breast cancer that is ErbB-2 overexpressed and has received treatment with anthracyclines, taxanes or trastuzumab in combination with capecitabine, and for the treatment of post-menopausal metastatic breast cancer that is hormone receptor positive, ErbB-2 overexpressed and suitable for hormone therapy in combination with letrozole. Lapatinib can effectively penetrate through a blood brain barrier, has irreplaceable importance for breast cancer patients with brain metastasis, and can effectively slow down disease progression.
However, up to 54.9% of lapatinib-dosed patients experience skin toxicity such as skin rash, acne dermatitis, itching, dry skin and desquamation. Their skin toxic reactions are often accompanied by significant epidermal damage, manifested as local or severe desquamation or even exfoliation of the epidermis. In addition, lapatinib can also cause liver function abnormality in patients with incidence rates as high as 37-53%, with grade 3-4 incidence rates of 2-6%, and even cases where patients die due to severe hepatotoxicity have been reported. Based on this, lapatinib has been warned by the U.S. FDA marker black box, and its hepatotoxicity problem needs to be particularly addressed.
At present, organ toxicity such as skin toxicity and liver toxicity induced by lapatinib lacks effective prevention and treatment means, and only dose reduction or drug discontinuation can be clinically adopted, so that the life quality of a patient is seriously affected, dose adjustment or treatment interruption can be caused, and tumor progress is finally caused. Therefore, the molecular mechanism of lapatinib causing organ toxicity is deeply researched, and effective therapeutic drugs are searched based on the molecular mechanism, so that the molecular mechanism has important practical significance for the safe, effective and wide clinical application of lapatinib.
Saikosaponin A is the root extract of Bupleurum scorzonerifolium of Umbelliferae, and is one of its main active ingredients. Research shows that saikosaponin A has various effects of depression resistance, tumor resistance, immunoregulation, organ protection and the like, and has good treatment effect and higher safety. However, no research shows that the pharmaceutical composition can be used for treating toxic and side effects caused by lapatinib.
Disclosure of Invention
The invention aims to provide a drug which can be used for relieving the toxic reaction induced by epidermal growth factor receptor inhibitor antitumor drugs such as lapatinib, and the toxic side effect caused by the single use of lapatinib is reduced by combined administration.
In order to achieve the purpose, the invention adopts the following technical scheme:
the invention provides application of saikosaponin A in preparing a medicament for relieving toxic and side effects of an Epidermal Growth Factor Receptor (EGFR) inhibitor. The CAS number of saikosaponin A is 20736-09-8, and the molecular formula is C 42 H 68 O 13 And the molecular weight is 780.98.
Further, the epidermal growth factor receptor inhibitor is lapatinib, gefitinib or afatinib.
In vitro cell experiments and in vivo experiments and researches on mice prove that the saikosaponin A has obvious inhibition effect on lapatinib-induced skin toxicity and hepatotoxicity, and can be used for treating lapatinib-induced skin toxicity and hepatotoxicity, so that the clinical application of lapatinib is expanded. In addition, saikosaponin A has therapeutic effect on skin toxicity caused by other EGFR inhibitors such as gefitinib and afatinib. Research shows that the saikosaponin A has specificity to toxic and side effects induced by EGFR inhibitors.
Furthermore, the toxic and side effects are skin toxicity or liver toxicity reaction caused by the administration of the epidermal growth factor receptor inhibitor.
Specifically, the skin toxic reaction is skin dryness, desquamation and inflammatory reaction caused by lapatinib, gefitinib or afatinib;
the hepatotoxic response is liver damage caused by lapatinib, gefitinib or afatinib.
Preferably, the dosage of the saikosaponin A is 5-20 mg/kg. The research shows that the medicine dosage is safe and effective.
The invention also aims to provide an anti-tumor combined medicament, which comprises a first preparation formed by the saikosaponin A and a pharmaceutically acceptable carrier, and a second preparation formed by the epidermal growth factor receptor inhibitor and the pharmaceutically acceptable carrier.
The invention provides an effective treatment medicament aiming at skin toxicity and liver toxicity induced by EGFR inhibitors such as lapatinib. Research shows that compared with the single group of lapatinib, the combined use of the saikosaponin A can obviously inhibit apoptosis of keratinocytes in epidermal tissues of mice and reduce epidermal tissue damage and liver damage of the mice. In addition, the dosage of the saikosaponin A is low, and the saikosaponin A has no influence on the conditions of animal survival, normal skin function and the like, which shows that the saikosaponin A is reasonable and safe as a protective agent and has higher feasibility.
Preferably, the molar ratio of the epidermal growth factor receptor inhibitor to the saikosaponin A is 0.05-4: 10-15.
The epidermal growth factor receptor inhibitor is lapatinib, gefitinib or afatinib.
Preferably, 190 mg/kg lapatinib and 5-20mg/kg saikosaponin A are used in combination.
The pharmaceutically acceptable carrier is a filler, a wetting agent, a binder, a disintegrant or a lubricant.
The medicament dosage form is a liquid preparation or a solid preparation, and comprises an oral solid preparation, an oral liquid preparation, an injection, a freeze-dried powder injection, a large infusion dosage form, a patch, an ointment, a gel, a soft capsule or a suppository.
The invention also provides application of the anti-tumor combined medicine in preparing an anti-breast cancer medicine.
The invention has the following beneficial effects:
(1) the invention provides a new application of saikosaponin A in preparing a preparation for treating EGFR inhibitor drug toxicity, and the saikosaponin A can obviously improve toxic side effects such as skin dryness, desquamation, inflammatory reaction, liver injury and the like caused by EGFR inhibitor drugs. The saikosaponin A is combined with EGFR inhibitor drugs, so that the toxic and side effects are effectively reduced, the safety of the EGFR inhibitor drugs is improved, and the clinical application of the EGFR inhibitor drugs is expanded.
(2) The saikosaponin A has low dosage, high safety and moderate price, can be prepared into proper dosage forms according to requirements, and has high clinical feasibility.
Drawings
Figure 1 is the keratinocyte survival rate reduced by saikosaponin a reversing lapatinib.
Fig. 2 is a representative graph of saikosaponin a inhibiting apoptosis of keratinocytes caused by lapatinib, wherein (a) is a representative graph of flow cytometry (PI/Annexin V staining method) for detecting apoptosis of keratinocytes after saikosaponin a combined with lapatinib, (B) is a statistical graph of apoptosis rate, and (C) is a representative graph of expression of apoptosis-related protein Cleaved PARP in keratinocytes after saikosaponin a combined with lapatinib.
FIG. 3 shows that saikosaponin A blocks gefitinib and afatinib-induced keratinocyte apoptosis.
FIG. 4 is the safety evaluation of the combination of saikosaponin A.
FIG. 5 shows that saikosaponin A improves lapatinib-induced skin toxicity, wherein (A) is an appearance image of abdominal skin of a mouse, and (B) is a level of mouse serum TNF alpha.
FIG. 6 shows that saikosaponin A inhibits apoptosis of mouse skin keratinocytes caused by lapatinib, wherein (A) shows staining of mouse skin tissue hematoxylin-eosin (H & E), and (B) shows staining of mouse abdominal skin tissue TUNEL.
Fig. 7 shows that saikosaponin a inhibits lapatinib from reversing lapatinib-induced liver injury in mice, (a) shows the content of liver injury marker ALT, and (B) shows the content of liver injury marker AST.
Detailed Description
The present invention is further illustrated by the following specific examples. The following examples are merely illustrative of the present invention and are not intended to limit the scope of the invention. It is intended that all modifications or alterations to the methods, procedures or conditions of the present invention be made without departing from the spirit or essential characteristics thereof.
The test methods used in the following examples are all conventional methods unless otherwise specified; the materials, reagents and the like used are, unless otherwise specified, commercially available reagents and materials.
Saikosaponin A (CAS number 20736-09-8) with molecular formula C 42 H 68 O 13 And the molecular weight is 780.98. Human keratinocytes HaCaT, purchased from guano europe biotechnology limited, guanzhou. Lapatinib (CAS number 231277-92-2) was purchased from ceramic biotechnology limited. Gefitinib (CAS number 184475-35-2), purchased from Dalian Meiren Biotech, Inc. Afatinib (CAS number 439081-18-2), purchased from MedChemexpress, Inc.
Example 1:
the human keratinocyte HaCaT is taken as a research object, 4 groups are set, and are respectively a control group, a lapatinib group, a saikosaponin A group and a combination group of saikosaponin A and lapatinib, the dose of lapatinib is 4 mu M, the dose of saikosaponin A is 15 mu M, and the control group is solvent dimethyl sulfoxide (DMSO). HaCaT cell viability was measured by SRB staining 24h after co-administration. The calculation formula is as follows: the cell survival rate of the administration group is (average absorbance value of the administration group cells)/(average absorbance value of the control group cells) × 100%.
The experimental results are specified below: as shown in fig. 1, the survival rates of HaCaT cells in the control group, lapatinib group, saikosaponin a group and the combined group are 100.00 ± 0.00%, 35.66 ± 3.14%, 102.88 ± 0.68% and 52.06 ± 2.30%, respectively, and the combined group has significantly improved cell survival rate (p ═ 0.0215) compared with the group with lapatinib acting alone, which indicates that the combined use of saikosaponin a can significantly improve the survival rate of keratinocytes under the action of lapatinib.
Example 2:
the human keratinocyte HaCaT is taken as a research object, 4 groups are set, namely a control group, a lapatinib group, a saikosaponin A group and a combination group of saikosaponin A and lapatinib, the dose of lapatinib is 4 mu M, the dose of saikosaponin A is 15 mu M, and the control group is solvent dimethyl sulfoxide (DMSO). After 24h of co-administration, the apoptosis rate was determined by flow cytometry in combination with Annexin V/PI staining.
The experimental results are specified below: flow cytometry combined with Annexin V/PI staining results (fig. 2A and 2B) showed that the apoptosis rates of HaCaT cells in the control group, lapatinib group, saikosaponin a group, and combined group were 8.33 ± 2.15%, 45.42 ± 2.42%, 6.50 ± 2.65%, and 23.93 ± 4.10%, respectively, and the combined group had a significantly reduced apoptosis rate (p ═ 0.0001) compared to the lapatinib-alone group, indicating that the use of saikosaponin a could significantly reverse lapatinib-induced keratinocyte apoptosis.
The human keratinocyte HaCaT is taken as a research object, 4 groups are set, namely a control group, a lapatinib group, a saikosaponin A group and a combination group of saikosaponin A and lapatinib, the dose of lapatinib is 4 mu M, the dose of saikosaponin A is 15 mu M, and the control group is solvent dimethyl sulfoxide (DMSO). After co-administration for 24h, total cell protein was obtained using IP lysis buffer and expression of apoptosis-related proteins was detected using Western Blot technique.
The Western Blot result (figure 2C) shows that when lapatinib is used alone to act on keratinocytes, the expression of apoptosis-related protein Cleaved PARP is remarkably increased, and after the saikosaponin A is used together, the expression level of the cell Cleaved PARP protein is remarkably reduced, which indicates that the lapatinib-induced apoptosis of the keratinocytes can be remarkably reversed by using the saikosaponin A.
Example 3:
the human keratinocyte HaCaT is taken as a research object, 6 groups are set, namely a control group, a saikosaponin A group, a gefitinib group, a combination group of gefitinib and saikosaponin A, an afatinib group and a combination group of afatinib and saikosaponin A, the dose of the saikosaponin A is 10 mu M, the dose of the gefitinib is 0.3 mu M, the dose of the afatinib is 0.05 mu M, and the control group is solvent dimethyl sulfoxide (DMSO). After co-administration for 24h, total cell protein was obtained using IP lysis buffer and expression of apoptosis-related proteins was detected using Western Blot technique.
The Western Blot result (figure 3) shows that after gefitinib or afatinib acts on keratinocytes alone, apoptosis-related protein clear PARP expression is remarkably up-regulated, and after the saikosaponin A is used together, the expression level of the cell clear PARP protein is remarkably reduced, which indicates that the saikosaponin A can remarkably reverse the apoptosis of the keratinocytes induced by other EGFR inhibitors. Suggesting that saikosaponin A may have therapeutic effect on skin toxicity caused by EGFR inhibitor.
Example 4:
20 female C57BL/6 mice aged 6-8 weeks and weighing 20-23g were randomly divided into 4 groups, which were a control group, lapatinib group, saikosaponin A group, and a combination of saikosaponin A and lapatinib, and 5 mice per group were administered continuously for 4 weeks in a gavage manner. The dosage of lapatinib is 950mg/kg/day, the dosage of saikosaponin A is 20mg/kg/day, and the control group is solvent normal saline. On day 27 of dosing, mice were anesthetized, weighed, and after removal of their abdominal hair, observed for symptoms of skin toxicity and photographed. Continuously administering for 1 day after the mouse is awakened, taking mouse serum and using an ELISA test kit to test the contents of an inflammation related factor TNF alpha and liver injury markers ALT and AST in the serum; the mice were then sacrificed to take abdominal skin tissue and observed for skin tissue damage and keratinocyte apoptosis using H & E staining and TUNEL staining.
The experimental results are specified below:
as shown in fig. 4, the combination of saikosaponin a restored the body weight of mice reduced by lapatinib, indicating that it is highly safe.
As shown in fig. 5A, the mice in the lapatinib-single administration group showed significant dryness and desquamation of the abdominal skin tissue, while the control group, the saikosaponin a group and the combination group did not show the above-mentioned phenomena, which indicates that the saikosaponin a can significantly improve the symptoms of lapatinib-induced dryness and desquamation of the skin. The ELISA results (fig. 5B) show that the contents of TNF α in the sera of the control group, lapatinib group, saikosaponin a group and the combined group of mice are 56.19 ± 1.72, 176.19 ± 17.84, 55.03 ± 19.18 and 66.77 ± 10.33pg/mL, respectively, and the content of TNF α in the combined group is significantly reduced (p <0.0001) compared with the single action group of lapatinib, which indicates that the combination of saikosaponin a can significantly improve the inflammation of the whole body of the mice induced by lapatinib.
The results prove that the saikosaponin A can obviously improve the skin toxicity reaction induced by lapatinib.
The H & E staining results (fig. 6A) of the abdominal skin tissues showed that the mouse epidermis of the lapatinib-alone administration group showed significant edema and keratinocyte condensation (yellow arrows), suggesting the occurrence of apoptosis, while the control group, saikosaponin a group, and the combination group did not show the above phenomenon, indicating that the combination of saikosaponin a could significantly reduce lapatinib-induced skin damage and keratinocyte apoptosis. The TUNEL staining results (fig. 6B) show that the numbers of green fluorescence positive cells in epidermal tissues of mice in the combination of saikosaponin a and lapatinib were significantly reduced compared to the lapatinib-administered group alone, indicating that the combination of saikosaponin a could inhibit lapatinib-induced keratinocyte apoptosis.
The results show that saikosaponin A can remarkably inhibit Lapatinib-induced keratinocyte apoptosis.
The biochemical results of the blood of the mice (fig. 7A) show that the content of the liver injury marker ALT in the serum of the mice of the lapatinib-single administration group is remarkably increased from 33.06 + -4.62U/L of the control mice to 79.36 + -32.68U/L (p is 0.0009), and the content of the ALT is remarkably reduced to 41.36 + -2.83U/L (p is 0.0046) after the combination of the saikoside. In addition, as shown in FIG. 7B, the content of AST (liver injury marker) in the serum of the mice of the lapatinib-single-administration group was significantly increased from 121.16 + -24.57U/L of the control mice to 320.44 + -93.02U/L (p <0.0001), while the content of AST was significantly decreased to 135.68 + -11.06U/L (p <0.0001) after the combination of saikoside.
These results demonstrate that saikosaponin a can significantly reverse lapatinib-induced liver damage at in vivo levels in mice.
Claims (10)
1. Application of saikosaponin A in preparing medicine for relieving toxic and side effects of epidermal growth factor receptor inhibitor is provided.
2. The use of claim 1, wherein the epidermal growth factor receptor inhibitor is lapatinib, gefitinib, or afatinib.
3. The use of claim 1, wherein the toxic side effects are skin toxicity or hepatotoxicity induced by administration of the epidermal growth factor receptor inhibitor.
4. The use according to claim 3, wherein the skin toxic response is a dry, desquamating and inflammatory response of the skin caused by lapatinib, gefitinib or afatinib;
the hepatotoxic response is liver damage caused by lapatinib, gefitinib or afatinib.
5. The use of claim 1, wherein saikosaponin A is used in a dose of 5-20 mg/kg.
6. An anti-tumor combined medicine is characterized by comprising a first preparation formed by saikosaponin A and a pharmaceutically acceptable carrier, and a second preparation formed by an epidermal growth factor receptor inhibitor and a pharmaceutically acceptable carrier.
7. The anti-tumor combination according to claim 6, wherein the molar ratio of the epidermal growth factor receptor inhibitor to saikosaponin A is 0.05-4: 10-15.
8. The anti-tumor combination according to claim 6, wherein the epidermal growth factor receptor inhibitor is lapatinib, gefitinib or afatinib.
9. The anti-tumor combination drug as claimed in claim 8, wherein 190 mg/kg of lapatinib and 5-20mg/kg of saikosaponin A are administered in combination.
10. Use of an anti-tumor combination as defined in any one of claims 6 to 9 for the preparation of a medicament against breast cancer.
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| CN104688760A (en) * | 2015-02-02 | 2015-06-10 | 山东省中医药研究院 | Pharmaceutical composition composed of saikoside A and taurine and use thereof |
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| CN104688760A (en) * | 2015-02-02 | 2015-06-10 | 山东省中医药研究院 | Pharmaceutical composition composed of saikoside A and taurine and use thereof |
| CN112673114A (en) * | 2018-09-13 | 2021-04-16 | 国立研究开发法人国立癌症研究中心 | Method for estimating breast cancer cell existence rate |
| CN110731965A (en) * | 2019-11-11 | 2020-01-31 | 西安交通大学 | Application of saikosaponin a in preparing medicine for preventing and treating psoriasis |
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