阅读说明：本技术 右旋龙脑作为阿霉素或其衍生物增敏剂在制备抗肺癌药物中的应用 (Application of d-borneol as adriamycin or derivative sensitizer thereof in preparation of anti-lung cancer drugs ) 是由 陈填烽 赖浩强 于 2018-10-17 设计创作，主要内容包括：本发明公开了右旋龙脑作为阿霉素或其衍生物增敏剂在制备抗肺癌药物中的应用。本发明发明人发现在添加了右旋龙脑后,非小细胞肺癌细胞A549对阿霉素的敏感性显著增加,右旋龙脑的应用能显著减少阿霉素的用量的同时保证阿霉素的疗效,从而达到降低阿霉素毒副作用的效果,保护人体正常细胞。因此,右旋龙脑作为阿霉素或其衍生物增敏剂在制备抗肺癌药物中的应用具有很好的应用价值。(The invention discloses application of d-borneol as a sensitizer for adriamycin or derivatives thereof in preparing anti-lung cancer drugs. The inventor finds that after the D-borneol is added, the sensitivity of the non-small cell lung cancer cell A549 to the adriamycin is obviously improved, and the application of the D-borneol can obviously reduce the using amount of the adriamycin and ensure the curative effect of the adriamycin, thereby achieving the effect of reducing the toxic and side effects of the adriamycin and protecting normal cells of a human body. Therefore, the application of the d-borneol serving as the sensitizer of the adriamycin or the derivative thereof in preparing the anti-lung cancer medicament has good application value.)

1. Application of d-borneol as a sensitizer for adriamycin or derivatives thereof in preparing anti-lung cancer drugs.

2. The use of d-borneol as a sensitizer for adriamycin or derivatives thereof for preparing anti-lung cancer drugs according to claim 1, wherein the sensitizer comprises: the d-borneol is natural d-borneol.

3. The use of d-borneol as a sensitizer for adriamycin or derivatives thereof for preparing anti-lung cancer drugs according to claim 1, wherein the sensitizer comprises: the derivatives comprise pyran doxorubicin and epidoxorubicin.

4. The use of d-borneol as a sensitizer for adriamycin or derivatives thereof for preparing anti-lung cancer drugs according to claim 1, wherein the sensitizer comprises: the components of the anti-lung cancer medicine comprise at least one of adriamycin and derivatives thereof and d-borneol.

5. The use of d-borneol as a sensitizer for adriamycin or derivatives thereof for preparing anti-lung cancer drugs according to claim 4, wherein the sensitizer comprises: the components of the anti-lung cancer medicine also comprise one or two of other components with treatment effect on lung cancer and pharmaceutically acceptable carriers.

6. The use of d-borneol as a sensitizer for adriamycin or derivatives thereof for preparing anti-lung cancer drugs according to claim 4 or 5, wherein: the ratio of the d-borneol to the adriamycin or the derivative thereof is 10-160 mu g to 0.03125-1 nmol.

7. The use of d-borneol as a sensitizer for adriamycin or derivatives thereof for preparing anti-lung cancer drugs according to claim 6, wherein the sensitizer comprises: the ratio of the d-borneol to the adriamycin or the derivative thereof is 40-160 mu g and 0.03125-1 nmol.

8. The use of d-borneol as a sensitizer for adriamycin or derivatives thereof for preparing anti-lung cancer drugs according to claim 7, wherein the sensitizer comprises: the ratio of the d-borneol to the adriamycin or the derivative thereof is 40-160 mu g: 0.15625-1 nmol.

9. The use of d-borneol as a sensitizer for doxorubicin or its derivatives according to claim 8 for the preparation of anti-lung cancer drugs, characterized in that: the ratio of the dextroborneol to the adriamycin is 40-160 mu g and 0.182-0.479 nmol.

10. The use of d-borneol as a sensitizer for doxorubicin or its derivatives according to claim 9 for the preparation of anti-lung cancer drugs, characterized in that: the ratio of the dextroborneol to the adriamycin or the derivative thereof is 160 mug: 0.25 nmol.

Technical Field

The invention belongs to the application of d-borneol, and particularly relates to the application of d-borneol as a sensitizer for adriamycin or derivatives thereof in preparing anti-lung cancer drugs.

Background

Doxorubicin (Doxorubicin, DOX) belongs to the anthracycline antimetabolites and is one of the most clinically effective and widely used antineoplastic drugs. Doxorubicin can intercalate directly into the DNA molecule in an additive fashion between base pairs, causing DNA damage. The chimeric DOX can cause the synthesis of DNA and RNA to be blocked, can inhibit the activity of topoisomerase and destroy the high-level structure of DNA, and is widely used for treating breast cancer, bladder cancer, lung cancer, ovarian cancer and the like. However, adriamycin has obvious toxic and side effects, particularly has myocardial toxicity, can cause heart failure when being serious, has primary and acquired drug resistance, and greatly influences the effect of chemotherapy, and the toxic and side effects of high-dose chemotherapy drugs cause patients to be difficult to tolerate or continue to finish treatment, thereby limiting the clinical application and the treatment efficiency of the adriamycin. At present, the research focus is to find an effective chemosensitizer for enhancing the anti-tumor effect of DOX and weakening or reversing the chemoresistance and toxic and side effects brought by DOX.

Lung cancer is currently the leading cause of tumor-related death in the world, and Non-small cell lung cancer (NSCLC) accounts for about 85% of lung cancer, with about 57% of NSCLC patients diagnosed with advanced (iiib or iv) lung cancer and thus lost the chance of surgical cure. Despite the diversity of therapeutic approaches, the overall survival of advanced non-small cell lung cancer is currently only 4-6 months with a 5-year survival rate of approximately 4.2%. For advanced NSCLC patients, platinum-containing dual-drug chemotherapy is still the standard first-line treatment scheme, but the curative effect of the current chemotherapy is bottleneck, the diseases of most patients still progress after chemotherapy, the benefit of the second-line treatment is more limited, and the total survival period is only 8-12 months. Therefore, based on the explanation of the drug resistance mechanism of the conventional antitumor drugs in modern medicine and biology, a novel chemosensitizer is searched for the treatment of lung cancer according to the principle of target point complementation, the synergistic effect of the chemosensitizer and the lung cancer treatment drugs is exerted, the clinical curative effect is enhanced, the toxic and side effects of the drugs are reduced, and the chemosensitizer has important scientific significance and application value.

Borneol (Borneol), commonly known as Borneol, is a terpene and bicyclic organic compound extracted from resin and volatile oil of Dipterocarpaceae plant, belongs to monoterpene alcohol, and is used for treating block pattern of coma, conjunctival congestion, sore throat, aphtha, sore and ulcer, unhealing after ulceration, coronary heart disease and angina pectoris. At present, although the d-borneol is reported to be used as an anti-tumor drug sensitizer, the effects and the effects of the d-borneol applied to different anti-tumor drugs and tumor cells are different, the existing documents do not report the d-borneol, and experimental data do not prove that the d-borneol sensitizes the adriamycin and has a remarkable effect of inhibiting the growth of the non-small cell lung cancer.

Disclosure of Invention

The invention aims to overcome the defects in the prior art and provides the application of d-borneol serving as a sensitizer for adriamycin or derivatives thereof in preparing anti-lung cancer drugs.

The purpose of the invention is realized by the following technical scheme: the application of the d-borneol as the sensitizer for the adriamycin or the derivative thereof in preparing the anti-lung cancer medicine is to use the d-borneol as the sensitizer for the adriamycin or the derivative thereof to assist the anti-lung cancer medicine.

The d-borneol is natural d-borneol.

The derivatives comprise pyran doxorubicin and epidoxorubicin.

The components of the anti-lung cancer medicine comprise at least one of adriamycin and derivatives thereof and d-borneol.

The components of the anti-lung cancer medicine also comprise one or two of other components with treatment effect on lung cancer and pharmaceutically acceptable carriers.

The preferable proportion of the D-borneol and the adriamycin or the derivative thereof is 10-160 mu g: 0.03125-1 nmol; more preferably 40-160 mug: 0.03125-1 nmol; more preferably 40-160 μ g, 0.15625-1 nmol; further preferably 40-160 mug, 0.182-0.479 nmol; most preferably 160. mu.g: 0.25 nmol.

Compared with the prior art, the invention has the following advantages and effects:

1. the invention discovers that the d-borneol serving as the adriamycin sensitizer can obviously reduce the dosage of the adriamycin while not influencing the anticancer activity of the adriamycin.

2. The invention discovers that the D-borneol can enhance the accumulation of the adriamycin in the A549 cells and the damage to mitochondria, can also enhance the apoptosis of the A549 cells mediated by caspase induced by the adriamycin, and can enhance the DNA damage mediated by the generation of active oxygen in the cells induced by the adriamycin, thereby playing a role in enhancing the anti-cancer activity of DOX.

Drawings

FIG. 1 is a graph showing the effect of natural d-borneol in combination with adriamycin on cell growth; wherein, the graph A is a bar graph of the inhibition effect of the adriamycin on the A549 cells under different concentrations of natural D-borneol, the graph B is a photo graph of the natural D-borneol combined with DOX for inhibiting the growth of the A549 cells, the graph C is a photo graph of the cells in the cell clone formation experiment, and the graph D is the cell clone number of the cell clone formation experiment.

FIG. 2 is a graph showing the accumulation of doxorubicin in A549 cells detected by fluorescence microscopy and flow cytometry; wherein, panel A is a cumulative photograph of intracellular DOX detected by fluorescence microscopy; panel B is a histogram of the distribution of flow cytometry detected intracellular DOX accumulation; panel C is a bar graph of DOX accumulation in cells over time following treatment with DOX alone and DOX in combination with native D-borneol.

FIG. 3 is a graph showing the effect of natural D-borneol on DOX-enhanced induction of caspase-mediated apoptosis in A549 cells; wherein, the graph A is a graph of detecting apoptosis by a flow cytometer, the graph B is a graph of activating intracellular Caspase protease activity by combining D-borneol and DOX, and the graph C is a graph of detecting the expression condition of the protein related to the apoptosis of A549 cells induced by enhancement of DOX by D-borneol by a Western blotting method.

FIG. 4 is a photograph showing the effect of the enhancement of DOX by natural d-borneol on the mitochondrial structure change of A549 cells under the observation of a fluorescence microscope.

FIG. 5 is a graph showing the results of the effect of natural d-borneol in synergy with DOX to induce ROS-mediated DNA damage in cells; wherein, the graph A is a graph of intracellular ROS accumulation conditions of different experimental groups, the graph B is a graph of labeled protein results of detecting DNA damage by Western blotting, the graph C is a graph of the results of verifying the effect of antioxidant NAC on inhibiting the activity of A549 cells by combining natural D-borneol and DOX, and the graph D is a graph of verifying that the antioxidant NAC reverses the apoptosis of the A549 cells by combining the natural D-borneol and the DOX.

FIG. 6 is a graph showing the results of experiments on the inhibition of the growth of mouse A549 subcutaneous tumors by natural d-borneol in cooperation with DOX; wherein, the graph A is a comparison graph of tumor volume increase of six experimental mice, the graph B is a comparison graph of tumor mass of six experimental mice after administration, the graph C is a comparison graph of weight change of six experimental mice, and the graph D is a graph of accumulated amount of DOX in organs of i.v. DOX, p.o.NB + i.v. DOX, i.v. NB + i.v. DOX; p.o. for oral gavage; i.v. means intravenous injection.

DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION

The present invention will be described in further detail below with reference to specific examples and drawings, but the embodiments of the present invention are not limited thereto.