CN113876761B - Application of phosphodiesterase 4 inhibitor ZL-n-91 in preparation of anti-osteosarcoma medicine - Google Patents
Application of phosphodiesterase 4 inhibitor ZL-n-91 in preparation of anti-osteosarcoma medicine Download PDFInfo
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Abstract
The invention provides application of a PDE4 inhibitor ZL-n-91 in preparing an anti-osteosarcoma medicament. The selective PDE4 inhibitor ZL-n-91 has the inhibitor strength of PDE4B and PDE4D over 5000 times that of other PDE family members, strong specificity and less side effects of vomit and the like; the results of in vitro cytology experiments show that ZL-n-91 can obviously inhibit the proliferation of osteosarcoma cells and has good development and application prospects.
Description
Technical Field
The application belongs to the field of antitumor drugs, and particularly provides application of a PDE4 inhibitor ZL-n-91 in preparation of an anti-osteosarcoma drug.
Background
Osteosarcoma (OS) is one of the most common malignant bone tumors, the incidence rate of the osteosarcoma is the first of primary bone tumors, and is better to be found in teenagers of 0-24 years old, and the incidence rate and incidence age of the osteosarcoma are more stable, and the incidence rate and incidence age of the osteosarcoma are more variable in the elderly. The survival rate of 5 years of osteosarcoma patients without metastasis at the initial diagnosis is between 40% and 75%. Local recurrence and distant metastasis are the most important causes of death in osteosarcoma patients. The local recurrence rate after osteosarcoma surgery is about 10% -20%. Once the tumor recurs, survival rates significantly decrease. About 10% to 20% of patients have distant metastasis at the first visit, 90% of them are lung metastases and about 50% of patients receiving conventional treatment have lung metastases. Once a patient's osteosarcoma has developed distant metastases, their 5-year survival rate drops to 20% -30%. In the past, the amputation operation mode is mostly adopted to radically remove the osteosarcoma affected limb, however, the amputation operation is not obvious to improve the long-term survival rate of the patient. Since the emergence of new adjuvant chemotherapy in the 70 th 20 th century, combined with extensive tumor resection, the 5-year survival rate of osteosarcoma patients was improved from 20% to 70% and the limb retention rate was improved from 20% to 80%. However, metastasis and recurrence of tumor cells remain the major cause of death in osteosarcoma patients. Thus, metastasis and recurrence are problems in osteosarcoma therapy. One major cause of tumor recurrence may be an increase in the number of Circulating Tumor Cells (CTCs), particularly some chemotherapy-resistant CTCs, which may be the source of post-treatment recurrence. Tumor self-seeding of CTCs is also thought to be responsible for tumor metastasis.
In recent years, gene-targeted therapy and immunotherapy methods for osteosarcoma have been developed, but the curative effect is not ideal, and the method is mostly only used for adjuvant therapy of chemotherapy-ineffective, recurrent and other advanced osteosarcoma, for example, apatinib can maintain the average progression-free survival period of metastatic osteosarcoma patients for about 6-12 months; in clinical study statistics of recent 30 years, it was found that the survival rate of OS patients 5 years after chemotherapy combined with limb protection surgery is about 70% and does not change significantly despite the use of measures such as increasing chemotherapy time and dose, applying targeting or immunotherapy, and the like. Therefore, the development of new anti-osteosarcoma drugs is still in great demand.
Phosphodiesterases (PDEs) have the function of hydrolyzing cAMP or cGMP, which are second messengers in cells, thereby influencing signal pathways mediated by the second messengers and regulating the functions of the cells. PDEs are divided into 11 subtypes, of which phosphodiesterase 4 (PDE 4) specifically hydrolyzes cAMP. PDE4 is mainly distributed in various inflammatory cells, including mast cells, macrophage lymphocytes, epithelial cells and the like, participates in the related physiological and pathological processes of promoting the activation of monocytes and macrophages, neutrophil infiltration, the proliferation of vascular smooth muscles, vasodilatation, myocardial contraction and the like, and has influence on the functions of the central nervous system, cardiovascular functions, inflammation/immune system, cell adhesion and the like. The research shows that the PDE4 inhibitor (PDE 4 i) has the effects of resisting inflammation, allergy and platelet activation. The action mechanism mainly relates to: 1) Inhibit the release of various inflammation mediators/cytokines, and can inhibit the expression of IL-4 and IL-5 genes; 2) Inhibiting activation of leukocytes (e.g., respiratory burst), inhibiting leukocyte migration; 3) Inhibiting expression or upregulation of cell adhesion factor (CAM); 4) Inducing the production of cells with inhibitory activity, such as IL-6; 5) Inducing apoptosis; 6) Stimulate the release of endogenous hormones and catecholamines. Although PDE4 inhibitors have been developed or are under development for diseases mainly Chronic Obstructive Pulmonary Disease (COPD), asthma, inflammatory bowel disease, arthritis and the like. However, many studies have shown that PDE4 inhibitors also have significant inhibitory effects on malignant tumors. Patricia Goldhoff can prolong the survival of mice by using PDE4 inhibitor after xenografting human brain astrocytoma cell U87 in nude mice. In 2006, motoshinNarita found that PDE4i can inhibit the growth of human melanoma cells, and PetrosX.E. Moratidis found that after PDE4 inhibitors CC-8075 and CC-8062 are added into pancreatic cancer cells, the cell proliferation and apoptosis of the pancreatic cancer cells can be reduced.
The existing PDE4 inhibitors mainly comprise Rolipram (Rolipram), cilomilast (Cilomilast), roflumilast (Roflumilast) and the like. The adverse reactions of gastrointestinal tracts, such as dizziness, headache, nausea, vomiting and the like, caused by Rolipram and Cilomilast influence the popularization and application of the medicine in clinic. One of the possible causes of adverse gastrointestinal reactions is the poor specificity of PDE4 inhibitors, which results in a moderately selective inhibition of the entire PDE family. For example, cilomilast has a Ki =92uM for PDE4, which is only 500 to 1000 times the Ki for PDE1, 2, 3, 5. Therefore, cilomilast can interact with other PDE family members at higher doses and produce side effects. In fact, the side effects of emesis at high doses are common in most PDE4 inhibitors. Roflumilast has been approved by the FDA in the united states for marketing for the treatment of COPD, reduction of inflammation in the lungs, resistance to oxidative stress, effective alleviation of fibrosis in the lungs, enhancement of mucosal clearance and airway remodeling, among others. But also has adverse effects, mainly manifested by diarrhea, weight loss, nausea, atrial fibrillation, and aggravation of mental diseases (such as insomnia, anxiety and depression).
Several novel PDE4 selective inhibitors have been developed to address the above problems, such as ZL-n-91, developed by Kyohimu, university of North Carolina:
the IC50 value of the polypeptide on PDE4D2 is 18nM, and the polypeptide has strong inhibiting effect on tumor necrosis factor alpha (TNF alpha) released by human peripheral blood mononuclear cells induced by lipopolysaccharide. Studies have shown that it inhibits PDE4D more than 5000-fold over other PDE family members. The ZLn-91 has higher selectivity on PDE4D, has small side effect, and can effectively avoid adverse reactions such as dizziness, nausea, vomit and the like. The application of the traditional Chinese medicine composition for treating lung diseases such as COPD and lung cancer and prostatic cancer has been tried at home and abroad, and good effects are achieved. The curative effect of the traditional Chinese medicine composition on other cancers is not verified by any actual research.
Disclosure of Invention
In the process of further expanding ZL-n-91 to treat various solid tumors and non-solid tumors, the applicant finds that ZL-n-91 has a good inhibition effect on osteosarcoma which is clinically difficult to treat at present. The invention researches the pathophysiology effect of ZL-n-91 by using in-vitro tumor cell culture and through cell proliferation experiments, cell cycle experiments and apoptosis experiments. The experiment proves that: the inhibitor can remarkably inhibit proliferation of human osteosarcoma cells U2OS, saoS-2 and MNNG/HOS; can obviously block the cell cycle of U2OS, saoS-2 and MNNG/HOS; can obviously induce the apoptosis of U2OS, saoS-2 and MNNG/HOS osteosarcoma cells. Lays a foundation for the research of preparing anti-osteosarcoma proliferation medicines.
In one aspect, the invention provides the use of the PDE4 inhibitor ZL-n-91 in the preparation of an anti-osteosarcoma medicament.
Further, the anti-osteosarcoma drug inhibits cell proliferation of osteosarcoma.
Further, the anti-osteosarcoma drug induces apoptosis of osteosarcoma cells.
Further, the medicine is in an oral or injection dosage form.
Further, the osteosarcoma is an orthotopic or metastatic osteosarcoma.
Further, the metastatic osteosarcoma is a pulmonary metastatic osteosarcoma.
In another aspect, the present application provides an anti-osteosarcoma agent comprising ZL-n-91.
Furthermore, ZL-n-91 is the only effective component in the anti-osteosarcoma medicine.
In another aspect, the present application provides a method of non-therapeutically inhibiting osteosarcoma cell proliferation comprising administering ZL-n-91.
Further, the osteosarcoma cell is U2OS, saoS-2 or MNNG/HOS.
Osteosarcomas described herein include various types of osteosarcomas of various characteristics, including, but not limited to, traditional osteosarcoma, intramedullary well-differentiated osteosarcoma, paraosteosarcoma, periosteal osteosarcoma, capillary-expanded osteosarcoma, and small cell osteosarcoma.
Oral and injectable dosage forms in the present application include, but are not limited to, tablets, capsules, oral liquid preparations, pills, granules, powders, water injections, oil injections, milk injections, powder injections and the like.
In addition to oral or injectable dosage forms, other known or under-developed dosage forms such as transdermal administration, inhalation administration, targeted carrier administration, may be routinely selected and designed by those skilled in the pharmaceutical arts as appropriate.
ZL-n-91 can be used in combination with other known or studied osteosarcoma-treating drugs or prepared into the same preparation, wherein the other osteosarcoma-treating drugs include but are not limited to chemotherapeutic drugs such as adriamycin, platinum, cyclophosphamide and methotrexate, and targeted drugs such as apatinib, aritinib, crizotinib, imatinib, nilotinib, cidinib and the like.
The phosphodiesterase 4 inhibitor ZL-n-91 of the present invention is commercially available, either as is, or is synthesized by itself or by itself in reference to the existing literature, and can be prepared synthetically, for example, in reference to Ruihong Ma, bin-yan Yang, chang-you Wu.A selective phosphodiesterase 4 (PDE 4) inhibitor ZL-n-91 supresses IL-17production by human memory 17 cells, international immunopharmacology,2008,8 (10): 1408-1417.
Has the advantages that: the selective PDE4 inhibitor ZL-n-91 can obviously inhibit the proliferation of tumor cells, indicates that the phosphodiesterase 4 inhibitor ZL-n-91 is expected to become an important target for anti-osteosarcoma proliferation research, provides a foundation for preparing anti-osteosarcoma proliferation medicines, and has good development and application prospects. ZL-n-91 has over 5000 fold greater potency as inhibitors of PDE4B and PDE4D as compared to other PDE family members. Compared with other PDE4 inhibitors, the compound has higher selectivity on PDE4B and PDE4D, strong specificity and small generated side effect, and can effectively weaken and even avoid adverse reactions such as vomit and the like.
Drawings
FIG. 1 is a graph showing the effect of ZL-n-91 on the inhibition of osteosarcoma cell proliferation: (a) Treating U2OS, saoS-2 and MNNG/HOS cells for 48h by ZL-n-91 with different concentrations to obtain a cell proliferation result graph; (b) OD values of U2OS, saoS-2 and MNNG/HOS cells at 0h, 24h, 48h, 72h and 96h are respectively detected by taking 200uM as an experimental concentration; all data are expressed as mean ± standard deviation. (n = 3), P <0.05, P <0.01, P <0.001and P <0.0001, all compared to the solvent control group;
FIG. 2 is the effect of ZL-n-91 on the cell cycle distribution of osteosarcoma: cell cycle flow assay of U2OS, saoS-2, MNNG/HOS cells treated with ZL-n-91 at 200uM for 48h; percentages of each stage of the cycle in U2OS, saoS-2, MNNG/HOS after 200uM ZL-n-91 treatment; all data are expressed as mean ± standard deviation; (n = 3), P <0.05, P <0.01, P <0.001and P <0.0001, all compared to the solvent control;
FIG. 3 is a graph of ZL-n-91 induction of apoptosis in osteosarcoma cells: carrying out apoptosis flow detection on U2OS, saoS-2 and MNNG/HOS cells for 48h by ZL-n-91 with different concentrations; percentage of different states of cells in U2OS, saoS-2, MNNG/HOS cells after treatment with ZL-n-91 at different concentrations; all data are expressed as mean ± standard deviation. (n = 3), P <0.05, P <0.01, P <0.001and P <0.0001, all compared to the solvent control group.
Detailed Description
In order to make the present invention more clear and intuitive for those skilled in the art, the present invention will be further described with reference to the accompanying drawings.
Example 1
CCK-8 method for detecting influence of ZL-n-91 on osteosarcoma cell proliferation
1) Taking the cells in logarithmic growth phase, namely U2OS, saoS-2 and MNNG/HOS, and preparing single cell suspension. The cells were seeded in 96-well plates at 100. Mu.L per well, and divided into 9 groups: complete control (no addition of any substance), solvent control (addition of equal volume of solvent EtOH), experimental (20 uM, 40uM, 80uM, 160uM, 320uM, 400uM, 480uM of EtOH in solvent dissolved ZL-n-91), 3 secondary wells per group;
2) After the plates are paved, adding ZL-n-91 with different concentrations into each group respectively, and continuously culturing the cells for 48h;
3) Adding 10ul of CCK-8 solution into each hole to avoid generating bubbles;
4) Continuously incubating the cells for 1-2 hours, taking out the culture plate, and measuring the absorbance at 450uM by using an enzyme-labeling instrument; and calculating the cell inhibition rate, and calculating the IC50 result by adopting Graphpad software. Cell growth inhibition (%) = (1-mean OD value of administration group/mean OD value of control group) × 100;
the results are shown in FIG. 1: with the increase of ZL-n-91 concentration, the proliferation capacity of osteosarcoma cells U2OS, saoS-2 and MNNG/HOS is remarkably reduced, and the inhibition effect is time-dependent.
Example 2
Flow cytometry for detecting influence of ZL-n-91 on cell cycle distribution of osteosarcoma
1) Taking U2OS, saoS-2 and MNNG/HOS cells in the logarithmic phase, re-suspending the cells by using a serum-free basic culture medium, inoculating the cells into a 6-hole culture plate at 2 x 105/ml, culturing the cells in a culture box at 2ml per hole, and performing starvation treatment for 24 hours;
2) After 24h, adding 200uM ZL-n-91, setting a solvent control group (adding EtOH with the same volume), and continuously culturing the cells for 48h;
3) Harvesting cells after 48h, washing with cold PBS for 2 times, preparing 1 × 106/mL cell suspension with PBS, adding 1mL70% absolute ethyl alcohol, and fixing at 4 deg.C or-20 deg.C for more than 24h;
centrifugation, cold PBS wash 2 times, according to kit instructions add 500 u L PE staining, gentle vortex cells, room temperature light-shielded incubation for 15min, modiFitLT5.0 software for cell cycle analysis.
The results are shown in FIG. 2: the cell cycle of U2OS and SaoS-2 is blocked in G0-G1 by 200uM ZL-n-91; MNNG/HOS cells were arrested in the G2-M phase.
Experimental example 3
Flow cytometry for detecting induction effect of ZL-n-91 on osteosarcoma apoptosis
Taking U2OS, saoS-2 and MNNG/HOS cells in logarithmic growth phase, inoculating 2 x 105 cells/ml into a 6-well culture plate, wherein each well is 2ml;
2) After the plates are paved, adding the experimental concentration ZL-n-91 (100uM, 200uM and 300uM) respectively, setting a solvent control group (adding EtOH with the same volume) at the same time, and continuously culturing the cells for 48h;
3) After 48h the cells were harvested, washed 2 times with cold PBS, prepared into 1 × 106/mL cell suspension with 1 × BindingBuffer, 100 μ L in flow tube, stained with 5 μ L7 AA-D and 5 μ L PE according to kit instructions, vortexed cells gently, incubated 15min at room temperature in the dark, followed by 400u1 × BindingBuffer in tube, flow cytometric assay in 1h, and analyzed by FlowJoV10 analysis software.
The results are shown in FIG. 3: ZL-n-91 can remarkably induce apoptosis of U2OS, saoS-2 and MNNG/HOS osteosarcoma cells.
The research results show that the phosphodiesterase 4 inhibitor ZL-n-91 adopted by the invention can inhibit osteosarcoma cell proliferation and has good anti-tumor effect.
The embodiments described above are presented to facilitate one of ordinary skill in the art to understand and practice the present invention. It will be readily apparent to those skilled in the art that various modifications to these embodiments may be made, and the generic principles described herein may be applied to other embodiments without the use of the inventive faculty. Therefore, the present invention is not limited to the embodiments described herein, and those skilled in the art should make modifications and alterations to the present invention in light of the present disclosure.
Claims (6)
- Application of PDE4 inhibitor ZL-n-91 in preparing anti-osteosarcoma medicine.
- 2. The use of claim 1, wherein the anti-osteosarcoma drug inhibits osteosarcoma cell proliferation.
- 3. The use of claim 1, wherein the anti-osteosarcoma drug induces apoptosis of osteosarcoma cells.
- 4. The use according to claim 1, wherein the medicament is in an oral or injectable dosage form.
- 5. The use according to any one of claims 1-4, wherein the osteosarcoma is an orthotopic or metastatic osteosarcoma.
- 6. The use of claim 5, wherein the metastatic osteosarcoma is a pulmonary metastatic osteosarcoma.
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| CN202010627545.0A CN113876761B (en) | 2020-07-01 | 2020-07-01 | Application of phosphodiesterase 4 inhibitor ZL-n-91 in preparation of anti-osteosarcoma medicine |
| PCT/CN2020/108212 WO2022000708A1 (en) | 2020-07-01 | 2020-08-10 | Use of phosphodiesterase 4 inhibitor zl-n-91 in preparation of anti-osteosarcoma medicament |
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Citations (3)
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| EP1828189A1 (en) * | 2004-11-29 | 2007-09-05 | Boehringer Ingelheim International GmbH | Substituted pteridines for treating inflammatory diseases |
| CN107041880A (en) * | 2016-02-05 | 2017-08-15 | 赵子建 | Phosphodiesterase 4 inhibitors ZL-n-91 is preparing anti-lung cancer propagation and the application in diversion medicaments |
| CN107714686A (en) * | 2016-08-10 | 2018-02-23 | 赵子建 | Applications of the phosphodiesterase 4 inhibitors ZL n 91 in treatment prostate cancer hyperplasia and diversion medicaments are prepared |
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|---|---|---|---|---|
| EP1828189A1 (en) * | 2004-11-29 | 2007-09-05 | Boehringer Ingelheim International GmbH | Substituted pteridines for treating inflammatory diseases |
| CN107041880A (en) * | 2016-02-05 | 2017-08-15 | 赵子建 | Phosphodiesterase 4 inhibitors ZL-n-91 is preparing anti-lung cancer propagation and the application in diversion medicaments |
| CN107714686A (en) * | 2016-08-10 | 2018-02-23 | 赵子建 | Applications of the phosphodiesterase 4 inhibitors ZL n 91 in treatment prostate cancer hyperplasia and diversion medicaments are prepared |
Non-Patent Citations (2)
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| Dexamethasone down-regulates cAMP-phosphodiesterase;Mikael Ahlstrom等;《Biochemical Pharmacology》;20050115;第69卷(第2期);全文 * |
| Phosphodiesterase 4 in osteoblastic osteosarcoma cells as a potential target for growth inhibition;Motoshi Narita等;《AntiCancer Drugs》;20030617;第14卷(第5期);摘要 * |
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