CN109331006B - Paclitaxel and elemene molecular compatible pharmaceutical composition and application thereof - Google Patents
Paclitaxel and elemene molecular compatible pharmaceutical composition and application thereof Download PDFInfo
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- 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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- 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
- A61K31/01—Hydrocarbons
- A61K31/015—Hydrocarbons carbocyclic
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- A—HUMAN NECESSITIES
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Abstract
The invention discloses an application of a paclitaxel and elemene molecule compatible pharmaceutical composition in preparing a medicament for treating taxane drug-resistant tumors, wherein the paclitaxel and elemene 1: 20 to 2000. The composition can be applied to treating breast cancer, lung adenocarcinoma, colon cancer, stomach cancer and prostate cancer, particularly has a remarkable effect of resisting taxol on treating taxane drug-resistant breast cancer, taxane drug-resistant lung adenocarcinoma and taxane drug-resistant colon cancer, can also remarkably reduce toxicity, greatly relieves the pain of tumor patients, provides a new strategy for treating drug-resistant tumors, and has important significance and wide application prospect on treating drug-resistant tumors.
Description
Technical Field
The invention relates to the field of pharmaceutical compositions, in particular to a paclitaxel and elemene molecular compatible pharmaceutical composition and application thereof in drug-resistant tumors.
Background
Taxanes such as paclitaxel and docetaxel are important components of tumor chemotherapy drugs and become first-line drugs in tumor chemotherapy, however, with the wide application of taxane drugs, the contradiction of drug resistance of tumors to paclitaxel is increasingly prominent.
The progression of many life-threatening diseases such as cancer is affected by a variety of mechanisms and, due to this complexity, the success of treatment with a single drug is limited, and therefore, combinations of drugs are often used to enhance the efficacy against cancer. For example, the research of poplar bud and the like finds that a rare ginsenoside component-paclitaxel multi-component system inhibits the proliferation and growth of lung cancer A549 cells by promoting paclitaxel to induce apoptosis, reduces the dosage of paclitaxel, and achieves the effects of reducing the toxicity of paclitaxel and enhancing the anti-lung cancer (poplar bud and the like, the experimental research of the rare ginsenoside component combined with paclitaxel to treat A549 lung cancer, Chinese traditional medicine J, 2018, 43 (7): 1446-one 1452.).
Elemene is an anticancer natural active component with good curative effect and small side effect, and is extracted and separated from curcuma zedoary, and the elemene comprises a plurality of elemene isomers such as alpha, beta, gamma and delta and mixtures of isomers in different proportions. Elemene is found to have the effects of inhibiting and killing various cancer cells, inducing the differentiation and apoptosis of tumor cells, inhibiting the infiltration and distant metastasis of the tumor cells, inhibiting the generation of tumor blood vessels and improving the anti-tumor immune response of organisms.
The research of the DONGYI and the like finds that the paclitaxel and elemene combined therapy has obvious clinical curative effect on treating advanced colon cancer, less adverse reaction, higher safety and high satisfaction of patients, and is worthy of wide popularization and application. [ Dongbei et al, application value of paclitaxel in combination with elemene in patients with advanced colon cancer, physicians in China Community, 2017, (28): 44-45].
However, the combination of paclitaxel and elemene has limited effect on treating tumors, has certain toxic and side effects, and particularly has poor effect on drug-resistant tumors, so the application range is small, and the performance needs to be improved.
Disclosure of Invention
The invention aims to provide the application of a paclitaxel and elemene molecular compatible pharmaceutical composition in preparing tumor drugs, which can greatly improve the drug resistance effect and curative effect of the drugs and can also reduce the dosage of paclitaxel so as to obviously reduce the toxic and side effects of the drugs.
In order to achieve the purpose, the invention adopts the following technical scheme:
the application of a paclitaxel and elemene molecular compatible pharmaceutical composition in preparing tumor drugs is disclosed, wherein the paclitaxel and elemene 1: 20 to 2000.
The elemene in the composition can inhibit the expression and transportation of P-glycoprotein to increase the accumulation of drugs, because the P glycoprotein can pump the drugs in cells out of the cells and reduce the drug concentration in the cells to ensure that the cells generate drug resistance; further influencing the biological pathways of the cells by influencing exocrine bodies to mediate RNAS for cell-to-cell information transfer; inducing apoptosis of tumor cells by down-regulating the membrane potential of mitochondria; inducing the change of cell permeability and enhancing the enrichment of the drug in the cells.
The invention prepares the pharmaceutical composition by paclitaxel and elemene according to the molecular compatibility theory and then applies the pharmaceutical composition to the preparation of tumor drugs, and determines the effective treatment proportion of the drugs by evaluating the curative effect and the drug resistance effect of the pharmaceutical composition prepared by paclitaxel and elemene molecules in the concentration range, thereby finding that the composition can enhance the curative effect and improve the drug resistance effect under the specific proportion.
Compared with the results of separately administering paclitaxel and elemene in the same proportion, the pharmaceutical composition of the invention can provide better antitumor activity and patient benefit rate after being administered to a subject; the pharmaceutical composition has a desired cytotoxic, cytostatic or biological effect on the relevant cells or tumor cells.
The elemene is any one of alpha-elemene, beta-elemene, gamma-elemene and delta-elemene isomers or a mixture of a plurality of elemene isomers in different proportions.
The paclitaxel and elemene molecule compatible pharmaceutical composition is applied to the preparation of drugs for treating taxane drug-resistant tumors.
The invention proves that the pharmaceutical composition has excellent curative effect on treating the taxane drug-resistant tumor through a great amount of experiments, because the elemene and the paclitaxel have combined action, the pharmaceutical composition can be cooperated in multiple targets and multiple ways, the accumulation of the drug is increased by inhibiting the expression and the transportation of the P-glycoprotein, the exocrine is influenced, the membrane potential of mitochondria is reduced, the apoptosis of tumor cells is induced, the change of the permeability of the cells is induced, the enrichment of the drug in the cells is enhanced, the affinity with the P-glycoprotein is reduced, and the capability of passing through a barrier is enhanced, so that the pharmaceutical composition has better anti-paclitaxel drug-resistant effect and can be used for treating the drug-resistant tumor.
The drug-resistant tumor is drug-resistant breast cancer, and the mass ratio of the paclitaxel to the elemene is 1: 20-2000, preferably the mass ratio of 1: 600 to 2000.
The increase multiple of the curative effect of the pharmaceutical composition on the drug-resistant breast cancer under the optimal mass ratio condition can reach 6.8 times compared with that of paclitaxel, which shows that the pharmaceutical composition has obvious synergistic drug-resistant breast cancer resistance in the mass range; under the condition of ensuring the curative effect, the dosage of elemene can be increased and the dosage of paclitaxel can be reduced, so that the drug composition can obviously enhance the drug resistance effect and simultaneously can obviously reduce the toxicity.
The drug-resistant tumor is drug-resistant lung adenocarcinoma, and the mass ratio of the paclitaxel to the elemene is 1: 20-2000, preferably the mass ratio of 1: 1000 to 2000.
The fold increase of the curative effect of the pharmaceutical composition on the drug-resistant lung adenocarcinoma under the preferable mass ratio condition compared with the paclitaxel can reach 5.4 times, which shows that the pharmaceutical composition has obvious synergistic drug-resistant lung adenocarcinoma effect in the mass range; under the condition of ensuring the curative effect, the dosage of elemene can be increased and the dosage of paclitaxel can be reduced, so that the drug composition can obviously enhance the drug resistance effect and simultaneously can obviously reduce the toxicity.
The drug-resistant tumor is drug-resistant colon cancer, and the mass ratio of the paclitaxel to the elemene is 1: 20-2000, preferably the mass ratio of 1: 1000 to 2000.
The curative effect of the pharmaceutical composition on drug-resistant colon cancer under the condition of the optimized mass ratio can be increased by 5.4 times compared with the taxol, which shows that the pharmaceutical composition has obvious synergistic drug-resistant colon cancer resisting effect in the mass range; under the condition of ensuring the curative effect, the dosage of elemene can be increased and the dosage of paclitaxel can be reduced, so that the drug composition can obviously enhance the drug resistance effect and simultaneously can obviously reduce the toxicity.
The invention also discloses application of the paclitaxel and elemene molecular compatible pharmaceutical composition in treating breast cancer, lung adenocarcinoma, colon cancer, gastric cancer or prostate cancer.
Compared with the prior art, the invention has the following beneficial effects:
(1) the paclitaxel and elemene molecule compatible pharmaceutical composition is applied to the preparation of tumor drugs, the drug resistance effect and the curative effect on various tumors are obviously improved, compared with the paclitaxel, the curative effect is improved by 4-7 times, especially the curative effect increase multiple of drug resistance breast cancer can reach 6.8 times, the curative effect increase multiple of drug resistance lung adenocarcinoma cells can reach 5.4 times, and the curative effect increase multiple of drug resistance colon cancer cells can reach 5.4 times, so that the composition has obvious effects of enhancing the curative effect of the paclitaxel and resisting the drug resistance of the paclitaxel under the condition of specific components;
(2) under the condition of ensuring the curative effect, the invention increases the dosage of elemene and reduces the dosage of paclitaxel, so that the drug composition can obviously reduce toxicity while obviously enhancing the drug resistance effect, greatly relieves the pain of tumor patients, provides a new strategy for drug-resistant tumor treatment, and has important significance and wide application prospect for the drug-resistant tumor treatment.
Drawings
FIG. 1 shows the ratio of paclitaxel to elemene (IC)50Ratio of corresponding concentration) breast cancer inhibition rate;
FIG. 2 shows the ratio of paclitaxel to elemene (IC)50Ratio of corresponding concentrations) drug-resistant breast cancer inhibition rate;
FIG. 3 shows the ratio of paclitaxel to elemene (IC)50Ratio of corresponding concentrations) lung adenocarcinoma inhibition rate;
FIG. 4 shows the ratio of paclitaxel to elemene (IC)50Ratio of corresponding concentrations) drug-resistant lung adenocarcinoma inhibitory rate;
FIG. 5 shows the ratio of paclitaxel to elemene (IC)50Ratio of corresponding concentrations) colon cancer inhibition rate;
FIG. 6 shows the ratio of paclitaxel to elemene (IC)50Ratio of corresponding concentrations) drug-resistant colon cancer inhibition rate;
FIG. 7 shows the ratio of paclitaxel to elemene (IC)50Ratio of corresponding concentration) gastric cancer inhibition rate;
FIG. 8 shows the ratio of paclitaxel to elemene (IC)50Ratio of corresponding concentration) prostate cancer inhibition rate.
Detailed Description
The invention will now be further illustrated by reference to specific examples, which are intended to be illustrative only and not to limit the scope of the invention.
Example 1
(1) Preparation of the test:
<1> culture of test cell line
Recovering frozen cells from liquid nitrogen tank, digesting, counting, diluting with culture medium to obtain suspension, standing at 37 deg.C and 5% CO2Culturing in an incubator.
<2> preparation of drug mother liquor
Respectively taking a taxol raw material medicament and an elemene raw material medicament, dissolving the taxol raw material medicament and the elemene raw material medicament by DMSO, and respectively taking a proper volume and diluting the proper volume by using a culture medium to prepare mixtures with different proportions.
(2) Procedure of the test
<1> digesting and counting the cells, preparing tumor cell suspension MCF-7, MCF-7/T (paclitaxel-resistant MCF-7 cells), A549, A549/T (paclitaxel-resistant A549 cells), HCT-8, HCT-8/T (paclitaxel-resistant HCT-8 cells), MGC-803 and PC-3, and adding 100 mul of cell suspension into each well of a 96-well cell culture plate;
<2>the 96-well cell culture plate is placed at 37 ℃ and 5% CO2Culturing in an incubator for 24 hours; diluting the drug with culture medium to required working solution concentration, adding 100 μ l corresponding drug-containing culture medium into each well, and setting up negative control group; the 96-well cell culture plate is placed at 37 ℃ and 5% CO2Culturing for 72 hours in an incubator;
<3> the 96-well plate was MTT stained, λ 490nm, and the OD value was measured according to the following procedure: mu.l MTT (5mg/ml) was added to each well and incubation was continued in the incubator for 4 hours; discarding the supernatant, adding 150 μ l DMSO into each well, and gently mixing by shaking for 10 min; λ 490nm, OD value per well was read by microplate reader, and cell inhibition rate was calculated according to the following formula.
Cell inhibition (%) was (negative control OD value-Experimental OD value)/negative control OD value X100%
According to the above method, measuring cell inhibition rate of paclitaxel and elemene, and calculating paclitaxel and elemene respectivelyElemene for IC50The values and the drug resistance index, and the specific results are shown in the following table 1.
TABLE 1 IC of paclitaxel, elemene50And drug resistance index
| Medicine | MCF-7 | MCF-7/T | A549 | A549/T | HCT-8 | HCT-8/T | MGC-803 | PC-3 |
| Paclitaxel IC50(nM) | 37.297 | 1930.027 | 25.131 | 1121.433 | 26.190 | 1078.214 | 22.904 | 38.381 |
| Resistance index | / | 51.7 | / | 44.6 | / | 41.2 | / | / |
| Elemene IC50(μM) | 834.769 | 1345.540 | 757.343 | 1384.027 | 927.306 | 1323.381 | 714.715 | 1127.370 |
| Resistance index | / | 1.6 | / | 1.8 | / | 1.4 | / | / |
As can be seen from Table 1, the paclitaxel-resistant cell lines have severe drug resistance to paclitaxel, the drug resistance index is 40-50 times, and elemene has little drug resistance to the paclitaxel-resistant cell lines.
Example 2
The method of example 1 was followed to calculate the paclitaxel ratio of the pharmaceutical composition for different tumor cellsIC50The values, specific results are shown in table 2 below; elemene IC of pharmaceutical composition for different tumor cells at different ratios50The values, specific results are shown in table 3 below.
TABLE 2 paclitaxel IC for various combinations of paclitaxel and elemene in different ratios50Comparison
TABLE 3 corresponding elemene IC for various combinations of paclitaxel and elemene in different ratios50Comparison
As shown in Table 2, the ratio of paclitaxel to elemene in the above composition of paclitaxel and elemene is 0.25:1 (IC)50Ratio of corresponding concentration), paclitaxel IC50The value is minimal.
As can be seen from Table 3, the ratio of paclitaxel to elemene in the above composition of paclitaxel and elemene is 0.25:1 (IC)50Corresponding concentration ratio), the dosage of elemene is larger, which indicates that the dosage of taxol can be reduced when the dosage of elemene is large.
Example 3
The results of the different ratios of paclitaxel and elemene compositions compared to the efficacy of paclitaxel and paclitaxel on different tumor cells according to the method of example 1 are as follows:
TABLE 4 comparison of the therapeutic effects of combinations of paclitaxel and elemene in different proportions
As can be seen from the above table, the compositions of paclitaxel and elemene with different ratios have improved therapeutic effect compared with paclitaxel for different tumor cells, when the concentration of elemene is greater than or equal to IC50When the concentration is higher, the curative effect is obviously improved.
For three drug resistant tumor cells, the ratio was 1:0.25 (IC)50Corresponding concentration ratio), the curative effect is increased most, compared with taxol, the curative effect is increased by 1.4 times for drug-resistant MCF-7 breast cancer cells, 1.4 times for drug-resistant lung adenocarcinoma cells and 1.5 times for drug-resistant colon cancer cells, the composition has obvious taxol-resistant effect, and the mass ratio of taxol to elemene corresponding to MCF-7/T, A549/T, HCT-8/T is respectively 1: 43,1: 74,1: 73.
for three drug resistant tumor cells, the ratio is 1:1 (IC)50Corresponding concentration ratio), the curative effect is increased most, compared with taxol, the curative effect is increased by 2.4 times for drug-resistant MCF-7 breast cancer cells, 1.9 times for drug-resistant lung adenocarcinoma cells and 2.0 times for drug-resistant colon cancer cells, the composition has obvious taxol-resistant effect, and the mass ratio of taxol to elemene corresponding to MCF-7/T, A549/T, HCT-8/T is respectively 1: 172,1: 295,1: 293.
for three drug resistant tumor cells, the ratio was 0.25:1 (IC)50Corresponding concentration ratio), the curative effect is increased most, compared with taxol, the curative effect is increased by 6.8 times for drug-resistant MCF-7 breast cancer cells, 5.4 times for drug-resistant lung adenocarcinoma cells and 5.4 times for drug-resistant colon cancer cells, the composition has obvious taxol-resistant effect, and the mass ratio of taxol to elemene corresponding to MCF-7/T, A549/T, HCT-8/T is respectively 1: 688,1: 1182,1: 1174.
FIGS. 1 to 8 show different ratios (IC)50Corresponding concentration ratio) of cabazitaxel and elemene, and the graphs of the inhibition rate of the drug composition on breast cancer, drug-resistant breast cancer, lung adenocarcinoma, drug-resistant lung adenocarcinoma, colon cancer, drug-resistant colon cancer, stomach cancer and prostate cancer can further illustrate that when elemene is in IC50Above concentration, the above 8 kinds of tumor cells have significant effect of enhancing the curative effect and the drug resistance of paclitaxel, and the effect is better when the dosage is larger.
Claims (4)
1. An application of a paclitaxel and elemene molecular compatible pharmaceutical composition in preparing tumor medicament is characterized in that the tumor is paclitaxel drug-resistant tumor; the preferable mass ratio of the paclitaxel to the elemene is 1: 600 to 2000; the tumor is breast cancer.
2. The use as claimed in claim 1, wherein the elemene is one or more of a mixture of various elemene isomers such as α -elemene, β -elemene, γ -elemene, δ -elemene, etc. in different proportions.
3. The use of claim 1, wherein the drug-resistant tumor is a drug-resistant lung adenocarcinoma, and the preferred mass ratio of paclitaxel to elemene is 1: 1000 to 2000.
4. The use of claim 1, wherein the drug-resistant tumor is a drug-resistant colon cancer, and the preferred mass ratio of paclitaxel to elemene is 1: 1000 to 2000.
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