The present invention relates to the application of a phosphodiesterase 4 (PDE4) inhibitor, in particular to application of PDE4 inhibitor ZL-n-91. The invention belongs to the field of tumor biology.
Prostate cancer is the most common malignant tumor in males in Europe and the United States. Prostate cancer ranks first in incidence and second only to lung cancer in mortality among males in the United States. Prostate cancer incidence has risen continuously in recent years in China, and the degree of histological malignancy of Chinese patients is higher than that of the United States patients. According to the survey of relative survival rate of patients with urologic cancer in Shanghai, 80.0%-90.0% of patients have developed to advanced prostate cancer at the time of diagnosis in china, with 5-year survival rate less than 30%. Due to the large population in China, the number of patients with prostate cancer increases dramatically, so it is necessary to improve prostate cancer prevention and treatment. Traditional treatments for prostate cancer include surgery, endocrine therapy, and radiotherapy and chemotherapy, but the therapeutic effect is not satisfactory. For recurrent prostate cancer, endocrine therapy with androgen deprivation is often adopted. The prostate cancer generally develops androgen-independence after 2-5 years of continuous endocrine therapy. The currently used therapy for patients with androgen-independent prostate cancer includes chemotherapy, radiotherapy, internal exposure to radionuclides and bisphosphonate treatment, etc., but the efficacy is not satisfactory. The treatment of prostate cancer is in a dilemma, and it is urgent to develop new treatments. Therefore, scientists and clinical experts are actively exploring safer and more effective treatments.
Phosphodiesterases (PDEs) have the function of hydrolyzing intracellular second messenger cAMP or cGMP, affecting the signaling pathways mediated by these second messengers and regulating the cell functions. PDEs include 11 subtypes, of which PDE4 specifically hydrolyzes cAMP. PDE4 is mainly distributed in various inflammatory cells, including mast cells, macrophage lymphocytes, epithelial cells, etc. It is involved in related physiological and pathological processes, including promoting monocyte and macrophage activation, neutrophil infiltration, proliferation of vascular smooth muscle, vasodilation and myocardial contraction, etc., having effects on central nervous system functions, cardiovascular functions, inflammation/immune system, and cell adhesion. Studies have shown that PDE4 inhibitors (PDE4i) have the functions of anti-inflammation, anti-allergy, and anti-platelet activation. Its main mechanisms include the follows: 1) inhibiting the release of various inflammatory mediators/cytokines, and inhibiting the expressions of IL-4 and IL-5 genes; 2) inhibiting the activation of leukocytes (such as respiratory bursts) and inhibiting leukocyte migration; 3) inhibiting the expression or up-regulation of cell adhesion molecules (CAM); 4) inducing to produce cytokines with inhibitory activity, such as IL-6; 5) inducing apoptosis; 6) stimulating the release of endogenous hormones and catecholamines.
Although PDE4 inhibitors that are underdevelopment or have been developed are mainly target on chronic obstructive pulmonary disease (COPD), asthma, inflammatory bowel disease, arthritis, etc., many studies have shown that PDE4 inhibitors have remarkable inhibitory effect on malignant tumors. Patricia Goldhoff heterotransplanted human brain astroglioma cell U87 into nude mice, and PDE4 inhibitors prolonged the survival time of tumor-bearing mice. In 2006, Motoshi Narita found that PDE4i could inhibit the growth of human melanoma cells. Petros X.E. Mouratidis found that the addition of PDE4 inhibitors CC-8075 and CC-8062 to pancreatic cancer cells could reduce cell proliferation and increase apoptosis.
The existing PDE4 inhibitors mainly include Rolipram, Cilomilast, Roflumilast, etc. As Rolipram and Cilomilast may induce dizziness, headache and gastrointestinal adverse reactions such as nausea and vomiting, their applications are limited. One of the possible causes of gastrointestinal side effects is the poor specificity of PDE4 inhibitors, which inhibits the whole PDE family. For example, Cilomitast inhibits PDE4 with Ki of 92 nM, only 500 to 1000 times of Ki for PDE1, 2, 3, and 5. Therefore, high dose of Cilomilast may interact with other PDE family members to cause side effects. In fact, it is common for most PDE4 inhibitors to cause side effect of vomiting at high doses. Although Roflumilast has been approved by US FDA for the treatment of COPD and it reduces lung inflammation, resists oxidative stress, effectively relieves fibrosis of the lungs and enhances mucosal clearance and rebuilds the airways, etc., it may produce some adverse reactions, mainly including diarrhea, weight loss, nausea, atrial fibrillation and aggravation of mental illness (such as insomnia, anxiety, depression), etc.
It is an object of the present invention to provide application of PDE4 inhibitor ZL-n-91 in preparing drugs for inhibiting prostate cancer proliferation.
In order to achieve the above object, the present invention adopts the following technical solutions.
The application of PDE4 inhibitor ZL-n-91 in preparing drugs for inhibiting proliferation of prostate cancer is within the scope of protection of the present invention.
In the present invention, in vitro tumor cell and subcutaneous xenograft models are used to study the pathophysiological effects of ZL-n-91. Experiments have confirmed that the inhibitor can significantly inhibit the proliferation of human prostate cancer PC-3 cells and the growth of transplanted tumors, which lays a foundation for preparing drugs which inhibit proliferation of prostate cancer.
The application of PDE4 inhibitor ZL-n-91 in preparing drugs for suppressing metastasis of prostate cancer is also within the scope of protection of the present invention.
The present invention studies the biological effects of ZL-n-91 using human prostate cancer cells PC-3. The experimental results show that the inhibitor can significantly inhibit the migration of prostate cancer cells, which lays a foundation for preparing drugs which suppress metastasis of prostate cancer.
The application of PDE4 inhibitor ZL-n-91 in preparing drugs for treating proliferation and metastasis of prostate cancer is also within the scope of protection of the present invention.
The routes of administration for the above applications is preferably oral, injection or inhalation.
The structural formula of the PDE4 inhibitor ZL-n-91 of the present invention is shown in the figure below.
The PDE4 inhibitor ZL-n-91 of the present invention can be directly purchased or synthesized. For example, it can be synthesized with reference to the literature [Ruihong Ma, Bin-yan Yang, Chang-you Wu. A selective phosphodiesterase 4 (PDE4) inhibitor Z1-n-91 suppresses IL-17 production by human memory Th17 cells. International Immunopharmacology, 2008, 8(10):1408-1417.]
In order to demonstrate the effects of the compounds in the present invention, in vivo xenograft growth inhibition experiments and in vitro cell experiments in mice are carried out in the following examples, to further elucidate the effects of PDE inhibitor ZL-n-91 of the present invention against proliferation and metastasis of prostate cancer.
The present invention can achieve the following beneficial effects. The selective PDE4 inhibitor ZL-n-91 of the present invention can significantly inhibit the proliferation and migration of tumor cells, indicating that the PDE4 inhibitor ZL-n-91 is expected to become an important target for inhibiting proliferation and metastasis of prostate cancer. It will lay a foundation for preparing drugs against proliferation of prostate cancer, presenting good prospect of application. The inhibitory effect of ZL-n-91 on PDE4D is more than 5,000 times that of other PDE family members. Compared with other PDE4 inhibitors, this compound has higher selectivity, specificity and fewer side effects for PDE4D, which can effectively reduce or even avoid adverse reactions such as vomiting.
The present invention can be further understood in combination with the following examples. However, those skilled in the art should appreciate that the description of the embodiments is only intended to illustrate the invention and should not be construed as limiting the invention as described in the claims.
The results were shown in
The resected tumors were fixed in 4% formalin overnight and embedded in paraffin for sectioning. Then the tumor proliferation antigen Ki67 was stained
As shown in
The results were shown in
The above results indicate that the PDE4 inhibitor ZL-n-91 used in the present invention can inhibit the proliferation and metastasis of prostate cancer cells, presenting a good anti-tumor effect.
Number | Date | Country | Kind |
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201610652824.6 | Aug 2016 | CN | national |
Filing Document | Filing Date | Country | Kind |
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PCT/CN2017/096399 | 8/8/2017 | WO | 00 |