Use of zedoarondiol in preparation of drug for preventing, treating, and inhibiting lung cancer

Abstract

The present invention relates to the technical field of traditional Chinese medicine. Disclosed is use of zedoarondiol in the preparation of a drug for preventing, treating, and inhibiting lung cancer. It has been discovered that zedoarondiol can effectively induce apoptosis of A549 cells, inhibit the growth of non-small cell lung cancer, significantly inhibit the migration of A549 cells, hinder the development of non-small cell lung cancer, and simultaneously inhibit tumor growth. The present invention provides new use of zedoarondiol, expanding the medical application of zedoarondiol and offering a new technical means for lung cancer treatment.

Description

Application of Curcuma zedoaria diol in the preparation of drugs for the prevention, treatment and inhibition of lung cancer

[0001] Priority Claim: This invention claims priority to Chinese Patent Application No. 2024105602576, filed on May 8, 2024, the entire contents of which are incorporated herein by reference. Technical Field

[0002] This invention relates to the field of traditional Chinese medicine technology, and in particular to the application of turmeric oxalool in the preparation of drugs for the prevention, treatment and inhibition of lung cancer. Background Technology

[0003] Lung cancer is the most common and threatening malignant tumor in humans today, characterized by high incidence, high metastasis rate, and high mortality rate, with a 5-year survival rate of only 18%. Therefore, the diagnosis and treatment of lung cancer has become a key research focus for modern medical researchers. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for approximately 85% of all lung cancer cases, making it a top priority in prevention and treatment research. NSCLC includes different pathological subtypes such as squamous cell carcinoma, adenocarcinoma, large cell lung cancer, and poorly differentiated variants, but the treatment and prognostic approaches are basically similar. Currently, the common approach is surgery as the primary treatment, supplemented by radiotherapy, chemotherapy, targeted therapy, or immunotherapy. Although these treatments can slow disease progression to some extent, they have serious side effects and drug resistance problems. Therefore, the need to develop new anti-tumor drugs is urgent.

[0004] Traditional Chinese medicine (TCM) has potential advantages in the field of cancer treatment due to its fewer side effects on the human body. Zedoary turmeric oil is a volatile oil extracted from the dried rhizome of Atractylodes lancea, containing components such as curcuminol, curcumidone, curcumenol, isocurcumenol, dehydrocurcumidone, turmeric glycol, and curcumenone. Studies have found that it has antiviral, anti-inflammatory, antitumor, and antibacterial effects, and also alters and enhances the immunogenicity of tumor cells, showing a certain therapeutic effect on lung cancer.

[0005] Research from Guangdong Pharmaceutical University has found that turmeric alcohol exhibits anti-tumor effects in both in vitro and in vivo experiments. For example, non-small cell lung cancer cells A549 and NCIH460 showed varying degrees of proliferation inhibition after treatment with different concentrations of turmeric alcohol for different durations. This inhibition was concentration- and time-dependent. Through exploration of its mechanism of action, it is believed that turmeric alcohol induces apoptosis in lung cancer cells through the ROS / JNK signaling pathway. At the same time, turmeric alcohol can also arrest the cell cycle in the G / M phase, leading to cell proliferation inhibition.

[0006] Due to its numerous components and unclear mechanism of action, Curcuma zedoaria oil cannot maximize its therapeutic effect. Currently, there are still very few single-component traditional Chinese medicines with clear therapeutic effects on lung cancer. There is an urgent need to discover more effective single-component traditional Chinese medicines for treating lung cancer and to provide more effective treatment options for lung cancer.

[0007] Zedoarondiol (CAS No. 98644-24-7) is an active ingredient in Curcuma zedoaria, with the following chemical structural formula:

[0008] Currently, its role in the treatment of lung cancer has not been reported. However, the inventors have found in their research that Curcuma zedoanediol has good therapeutic activity for lung cancer. In view of this, the present invention provides the application of Curcuma zedoanediol in the preparation of drugs for the treatment of lung cancer, with fewer side effects. Summary of the Invention

[0009] The purpose of this invention is to provide the application of turmeric oxalone diol in the preparation of drugs for the prevention, treatment and inhibition of lung cancer, with definite efficacy and few side effects.

[0010] To achieve the above-mentioned objectives, the technical solution of this invention is as follows:

[0011] This invention provides the application of turmeric oxalone diol in the preparation of drugs for the prevention, treatment and inhibition of lung cancer.

[0012] Preferably, the lung cancer is a mammalian lung cancer (including human and non-human mammals).

[0013] Preferably, the lung cancer is at least one of small-cell carcinoma and non-small cell lung cancer.

[0014] More preferably, the lung cancer is non-small cell lung cancer.

[0015] Preferably, the lung cancer is at least one of lung adenocarcinoma, lung squamous cell carcinoma, large cell lung cancer, lung adenosquamous carcinoma, and salivary gland tumor.

[0016] Preferably, the prevention, treatment, and inhibition of lung cancer are at least one of the following: inhibiting the proliferation rate of lung cancer cells, altering the cell cycle distribution of lung cancer cells, promoting lung cancer cell apoptosis, inhibiting the migration ability of lung cancer cells, and inhibiting the growth of lung cancer tissue.

[0017] Preferably, the prevention, treatment, or inhibition of lung cancer is at least one of promoting lung cancer cell apoptosis, inhibiting the migration ability of lung cancer cells, and inhibiting the growth of lung cancer tissue.

[0018] Preferably, the prevention, treatment, and inhibition of lung cancer involves simultaneously promoting lung cancer cell apoptosis, inhibiting the migration ability of lung cancer cells, and inhibiting the growth of lung cancer tissue.

[0019] Preferably, in the application, turmeric oxalool can be used simultaneously with other anticancer agents.

[0020] Examples of the anticancer agents mentioned include: acivicin, aclarubicin, acodazole hydrochloride, acronin, aldesleukin, altretamine, ambomycin, ametantrone acetate, aminoglutethimide, amsacrine, anastrozole, antramycin, asparaginase, asperlin, azacitidine, azetepa, azotomycin, batimastat, benzodepa, bicalutamide, bisantrene hydrochloride, bizelesin, and bleomycin sulfate. sulfate, brequinar sodium, bropirimine, calusterone, caracemide, carbetimer, carboplatin, carmustine, carrubicin hydrochloride, carzelesin, cedefingol, chlorambucil, cilolemycin, fluorouracil, flurocitabine, fosquidone, iproplatin, irinotecan hydrochloride, lanreotide acetate, letrozole, liarozole hydrochloride, lometrexol Sodium, lomustine, losoxantrone hydrochloride, masoprocol, maytansine, mechlorethamineHydrochloride, megestrol acetate, melengestrol acetate, melphalan, menogaril, mitosper, mitotane, mitoxantrone hydrochloride, mycophenolic acid, nocodazole, nogalamycin, ormaplatin, oxisuran, paelitaxel, pegaspargase, peliomycin, pentamustine, peplomycin sulfate, perfosfamide, pipobroman, piposulfan, piroxantrone hydrochloride hydrochloride, plicamycin, promethene, porfimer sodium, porfiromycin, prednimustine, procarbazine hydrochloride, puromycin, pyrazofurin, riboprine, rogletimide, safingol, safingol hydrochloride, semustine, simtrazene, sparfosate sodium, sparsomycin, vapreotide, verteporfin, andrographolide, atrimustine, axinastatin 1, axinastatin 2 2) Marine cyclic peptide 3 (axinastatin)3) Azasetron, azatoxin, azatyrosine, batimastat, carboxyamidotriazole, cicaprost, dacliximab, ganirelix, lanreotide, lovastatin, loxoribine, lurtotecan, miltefosine, mofarotene, and tirapazamine.

[0021] The beneficial effects of this invention are as follows:

[0022] (1) This invention provides the application of curcuminone diol in the preparation of drugs for treating lung cancer, discovers a new use of curcuminone diol, expands the application of curcuminone diol in medicine, and provides a new technical means for the treatment of lung cancer.

[0023] (2) The experimental results of this invention show that Curcuma zedoaria diol can effectively induce apoptosis of A549 cells, inhibit the growth of non-small cell lung cancer, and significantly inhibit the migration of A549 cells, thus hindering the development of non-small cell lung cancer and inhibiting tumor growth. Attached Figure Description

[0024] Figure 1 shows the effect of turmeric oxalool on the viability of A549 cells in Example 1. Compared with the control group, ****p<0.0001, ***p<0.001, **p<0.01, and *p<0.05.

[0025] Figure 2 shows the effect of turmeric oxalool on the wound healing rate of A549 in Example 2. Compared with the control group, [the results are shown in Figure 2]. ＊＊ p<0.01, ＊ p<0.05.

[0026] Figure 3 shows the effect of each drug on the tumor diameter in nude mice in Example 3.

[0027] Figure 4 shows the effect of each drug on the tumor weight of nude mice in Example 3.

[0028] Figure 5 shows the effects of each drug on spleen weight (spleen weight) in nude mice in Example 3. Compared to the control group, ＊＊ p<0.01; compared with the model group, #p<0.05.

[0029] Figure 6 shows the effects of each drug on tumor weight in nude mice in Example 3. Compared to the control group, ＊＊ p<0.01; compared with the model group, #p<0.05, ##p<0.01.

[0030] Among them, “Control”, “con”, and “CON” all refer to the blank group;

[0031] Both “Zedoarondiol” and “Zed” refer to the turmeric oxalool diol treatment group;

[0032] “Model” refers to a group of models;

[0033] "5-FU" refers to the positive drug treatment group;

[0034] “Cur” refers to the curcuminol treatment group;

[0035] "Zedoary Turmeric Oil" and "ZTO" both refer to the treatment group of turmeric oil. Detailed Implementation

[0036] The following non-limiting embodiments are intended to enable those skilled in the art to gain a more comprehensive understanding of the present invention, but do not limit the invention in any way. The following content is merely an exemplary description of the scope of protection claimed by the present invention, and those skilled in the art can make various changes and modifications to the invention based on the disclosed content, which should also fall within the scope of protection claimed in this application.

[0037] The present invention will be further described below by way of specific embodiments. Unless otherwise specified, all chemical reagents used in the embodiments of the present invention are obtained through conventional commercial means. Unless otherwise specified, all operating methods and equipment used are conventional, and the equipment and materials used in each embodiment are the same. Unless otherwise stated, all percentages, ratios, and proportions herein are by weight. Unless otherwise stated, all temperatures are in Celsius (°C).

[0038] The zedoarondiol used in this invention has CAS number 98644-24-7 and its chemical structural formula is as follows:

[0039] Example 1

[0040] 1. Materials

[0041] 1.1 Experimental Cells

[0042] The human non-small cell lung cancer cells—A549 cells—were purchased from Wuhan Pronosei Biotechnology Co., Ltd.

[0043] 1.2 Drugs

[0044] Curcuma zedoaria diol was prepared in-house with a purity of ≥98%.

[0045] 1.3 Reagents

[0046] Ham's F-12K medium (PM150910, Pronosai), trypsin (0458) was GIBCO; DMSO (D-5879, Sigma), CCK8 (CK04, Dongren Chemical Technology Co., Ltd.).

[0047] 1.4 Instruments

[0048] MCO175 CO2 incubator (Sanyo); Sh1 inverted microscope (OLYMPUS); SYNERGY™ 4 microplate reader (BioTek).

[0049] 2. Method

[0050] 2.1 Cell Culture

[0051] Resuscitate cells and culture them in normal medium at 37°C with 5% CO2. After two passages at a 1:3 ratio, collect cells at various growth stages, digest with trypsin, and adjust the cell concentration to 1×10⁶ cells / mL. 5 The cells / mL were inoculated into 96-well plates, 6-well plates, and 10cm petri dishes, and the medium was changed after 24 hours for subsequent experiments.

[0052] 2.2 Drug Concentration Determination

[0053] The experiment was divided into a normal control group and various dosage groups of turmeric oxaliplatin. The drug dosages were set as follows: 2mM, 1mM, 0.5mM, 0.25mM, 0.125mM, and 0.0625mM.

[0054] After culture, the cells were washed three times with PBS. The control group was treated with Ham's F-12KD, the negative control group with Ham's F-12KD and DMSO (0.1%), and the drug group with Ham's F-12KD and the drug. Before adding the drug, it was dissolved in DMSO to a concentration of mmol / mL, and then diluted 1:1000 with the culture medium (Ham's F-12KD) to achieve the target dose in mM.

[0055] 2.3 Determination of cell viability

[0056] After the drug was applied for 24h, 48h, and 72h, 100μL of CCK8 solution was added to each well of a 96-well plate and incubated in an incubator for 2-4h. The 96-well plate was then placed on a shaker and shaken at low speed for 10min. The OD value was detected at a wavelength of 450nm using an ELISA reader.

[0057] 2.4 Statistical Methods

[0058] Quantitative data are expressed as mean and standard deviation. Western blot images were analyzed using nonparametric tests via ImageLab. All statistical data were analyzed using GraphPad Prism software (San Diego, CA). One-way ANOVA was used to analyze comparisons among multiple groups. t-tests were performed to analyze inter-group comparisons. A p-value <0.05 was considered statistically significant.

[0059] The experimental results are shown in Figure 1. The results indicate that turmeric diol can significantly induce apoptosis in A549 cells at a concentration of 1 mM (P<0.05).

[0060] Example 2

[0061] 1. Materials (same as in Example 1)

[0062] 2. Experimental Methods: A549 non-small cell lung cancer cells were cultured in 6-well plates. After the cells grew to 5 x 10⁵, a straight line was gently drawn on the culture dish using the tip of a sterile 200 μL pipette. The dish was gently shaken to wash away floating cells in the drawn area with culture medium. 2 mM turmeric ketone diol was added to each well. A control group was set up without turmeric ketone diol. Before treatment with turmeric ketone diol, the initial state of the drawn area was photographed and recorded using an inverted microscope. The cells were then cultured in culture medium containing turmeric ketone diol for different treatment times (6 hours, 12 hours, and 24 hours). The state of the drawn area was photographed and recorded at each time point using an inverted microscope. By comparing the images before and after the experiment, the effect of turmeric ketone diol on the migration ability of A549 non-small cell lung cancer cells was evaluated.

[0063] Six to eight horizontal lines were randomly drawn, and the mean intercellular distance or mean scratch area was calculated to quantitatively analyze the inhibitory effect of turmeric oxalone diol on cell migration ability.

[0064] Wound healing rate (cell migration rate) = (initial scratch area - scratch area at time t) / initial scratch area. Experimental results: As shown in Figure 2, turmeric oxalool significantly inhibited the migration ability of A549 cells.

[0065] Example 3

[0066] Experimental methods:

[0067] Experimental animals: BALB / c-nu nude mice, weighing 20±2g.

[0068] Husbandry method: All animals are kept in plastic cages in a stable environment with a 12 / 12h light / dark cycle and free access to tap water and food. All animals acclimatize for one week at 25℃ and air humidity maintained at 40%-60%.

[0069] drug:

[0070] Curcuma zedoaria diol;

[0071] Positive control drug 5-Fluorouracil (5-fluorouracil; 5-FU): 20 mg / kg (calculated according to the instructions).

[0072] Curcumenol (C 15 H 22 O2 (Cur) was purchased from Chengdu Purifa Co., Ltd., product number BP0420, 300 mg / kg, molecular formula:

[0073] Zedoary Turmeric Oil (ZTO) was purchased from Shanghai Yuanye Biotechnology Co., Ltd., product number S27690, 240mg / kg.

[0074] Grouping method: Nude mice were randomly divided into groups after 7 days of acclimatization. Animals in the model group and each treatment group received a subcutaneous injection of 5 × 10⁻⁶ ppm in their left forelimb. 6 A549 cells were collected to observe tumor formation.

[0075] After tumor formation, animals in each treatment group were treated with the corresponding dose of drug via gavage at a volume of 10 mL / kg, once a day for 14 consecutive days. The model group and the normal control group were given the same volume of physiological saline in the same manner. Throughout the process, animal weight and tumor diameter were measured every 3 days.

[0076] Experimental Results: After tumor formation in nude mice, the mice were treated with the drug. The results are shown in Figures 3-6. Compared with the model group, the tumor growth in the positive control group and each dose group was very slow, especially in the positive control group and the high-dose group. Curcuminol and Curcuma oil, which have a similar structure to Curcuminone diol, did not have significant anti-tumor effects.

[0077] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. Application of Curcuma zedoaria diol in the preparation of drugs for the prevention, treatment and inhibition of lung cancer.

2. The application according to claim 1, characterized in that, The lung cancer mentioned refers to lung cancer in mammals.

3. The application according to claim 1, characterized in that, The lung cancer is at least one of small cell lung cancer and non-small cell lung cancer.

4. The application according to claim 3, characterized in that, The lung cancer in question is non-small cell lung cancer.

5. The application according to claim 1, characterized in that, The lung cancer is at least one of the following: lung adenocarcinoma, lung squamous cell carcinoma, large cell lung cancer, lung adenosquamous carcinoma, and salivary gland tumor.

6. The application according to claim 1, characterized in that, The prevention, treatment, and inhibition refer to at least one of the following: inhibiting the proliferation rate of lung cancer cells, altering the cell cycle distribution of lung cancer cells, promoting lung cancer cell apoptosis, inhibiting the migration ability of lung cancer cells, and inhibiting the growth of lung cancer tissue.

7. The application according to claim 6, characterized in that, The prevention, treatment, and inhibition mentioned refer to at least one of the following: promoting lung cancer cell apoptosis, inhibiting the migration ability of lung cancer cells, and inhibiting the growth of lung cancer tissue.

8. The application according to claim 7, characterized in that, The prevention, treatment, and inhibition methods involve simultaneously promoting lung cancer cell apoptosis, inhibiting the migration ability of lung cancer cells, and suppressing the growth of lung cancer tissue.

9. The application according to claim 1, characterized in that, In this application, turmeric oxalool and other anticancer agents are used simultaneously.

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