Function And Mechanism Of Anti-prostate Cancer Growth And Metastasis Of Chinese Medicinal Monomer And Formula

Prostate cancer (PCa) remains the most common malignant tumor in men older than 50 years worldwide and accounts for the first leading incidence and the second leading cause of cancer-related deaths in western developed societies. In China, the incidence of PCa increases with a rapid growth rate of 10% per year in recent years. With the gradual steps into an aging society, a peak incidence may occur over the next decade in Chinese old men. Because of prostate’s hidden location in anatomy, PCa is difficult to detect in early stage. Once diagnosed, the majority of patients have lost the most appropriate opportunities for radical treatment. The early stage PCa can be treated by radical surgery, such as removal of the testicles. However, once PCa progressed to the advanced stage, it becomes incurable and the main treatment choices rely on the endocrine therapy (also called the androgen deprivation therapy). Although this therapy has a certain efficacy in tumor control initially, the efficacy generally maintains only 1.5-4 years and treatment failure remains eventually inevitable, thus the castration-resistant prostate cancer (CRPC) realizes its further development and the tumors metastasize to some other target organs beyond prostate. The treatment of metastatic CRPC has been a difficult area in the field of PCa research.Among the three treatment strategies of PCa, chemotherapy has always played an important role. However, although new chemotherapy drugs emerge and new chemotherapies continue to improve in recent years, anti-prostate cancer drugs still hold some adverse problems such as widespread poor drug targeting and systemic toxic ity, which limit the long-term efficacy of drugs. The multiple resistance to anti-cancer drugs exhibited by PCa is the main reason of tumor recurrence, metastasis and treatment failure and this problem is also the most insurmountable difficulty for clinical treatment of PCa. Currently, the effectiveness of commonly used chemotherapy drugs for PCa is not so satisfactory, which makes it an important and rationale strategy to excavate bioactive ingredients from natural products for the development of anti-prostate cancer drugs. Herbal ingredients are main source of modern medication and 70% of the anti-cancer drugs approved onto the market by FDA are originated from natural plants, which suggest that the development of anti-cancer drugs from traditional medicine is a feasible and successful program for modern medication. The Traditional Chinese Medicine (TCM) is a traditional medicinal resource in China with our unique advantages. China has an abundant resource reserves of medicinal plants, thus it will be a broad range of application prospects for the excavation of traditional Chinese medicine monomer and for the invention of Chinese medicinal formula, both of which all exhibit the activity of anti-prostate cancer for prostate cancer drug development. Under the guidance of TCM theory and the principle of formula compatibility of monarch, minister, assistant and guide and combined with experimental methods of modern science and biology, it’s promising to elucidate the exact pharmacological and molecular mechanism of Chinese medicine monomer and Chinese medicinal formula, and this also shed new lights on the research and drug development of PCa.The Chinese medicine monomer Lycorine belongs to isoquinoline alkaloids extracted from the perennial medicinal plant Lycoris of Amaryllidaceae genera that widely distributed in China. Recently, many researches have reported Lycorine’s various excellent biological activities including analgesic, antipyretic, anti-inflammatory, sterilize, antiviral, hypotensive, antimalarial and anti-tumor. Lycorine’s chemical structure possesses a typical tetracyclic skeleton, which is held by a large class of Lycorine-type alkaloids. Besides, Lycorine exhibits ideal biosafety. Therefore, the chemical synthesis and biological activity of Lycorine attract extensive research interests of numerous chemists and biologists for decades, which represents far-reaching value of medical research implications in both medicinal chemistry and biology.The Chinese medicinal formula holds many advantages such as multi-channel, multi-target and few side effects, thus it has been a new hotspot in the drug development area of tumor treatment and adjuvant therapy in our country. TCM’s inhibition in tumor growth and metastasis has always been an important aspect of its anti-tumor activities. The in vivo tumor growth and metastasis is a dynamic process consisting of a variety of carcinogenic factors, such as oncogenes and tumor promoters and the interactions between them. As such, to uncover the anti-tumor mechanism of Chinese medicinal formula from the in vitro cellular lever, from the in vivo animal model lever and from the biochemical and molecular biological level will be more beneficial for the development of new anticancer drugs. However, there is few reports about Chinese medicinal formula’s anticancer pharmacological activity in such abovementioned research levels in the domestic and overseas.The evolution of tumor is a complex multi-step process, within which the cell immortalization resulted from cell cycle regulation disorder and the blocked cell apoptosis and consequent greatly enhanced capability of tumor cell migration and invasion form the cellular basis of cancer. This immortalization and enhanced metastatic and invasive capability have intensive relationship with tumogenesis, tumor progression, metastasis and prognosis. Thus, drugs that target cell cycle, cell apoptosis, migration and invasion represent the main aspects of their anti-cancer mechanisms. What’s more, as body’s first line of defense against disease, the immune system plays vital roles in tumor cell identification and removal. Numerous studies have shown that there are different degrees of immune dysfunction in cancer patients and that it is favorable to enhance immune function for anti-cancer. T cells occupy extremely important position in body’s anti-tumor immune responses. If candidate drugs can stimulate immune cell differentiation or hyperplasia and therefore induce specific anti-tumor immune responses, it will be of great significance for these drugs to combat cancer.To determine the exact anti-prostate cancer bioactivities and molecular mechanisms of Chinese medicine monomer Lycorine and the Chinese medicinal formula that invented in this research, we investigated the effects on PCa of both Lycorine and this formula from the in intro level, in vivo level and the biochemical level. Through comprehensive literature survey and by retrieving traditional anti-tumor Chinese medicine prescriptions, we conducted the screening, determination and verification of some TCM deviated natural product compounds and medicinal formulas and finally figured out the anti-prostate cancer activities of Lycorine and the Chinese medicinal formula that invented in this research. Considering the Chinese medicine theory, the therapeutic principle and the pathogenesis mechanism of PCa, we utilized some experiments such as MTS assay, flow cytometry, colony formation, migration assay, invasion assay, immunofluorescence staining, Real time-PCR, Quantitative-PCR, western blotting, immunohistochemistry, chromatin immunoprecipitation and RNA interference as well as the nude mice subcutaneous xenograft model and the nude mice orthotopic prostate cancer xenograft model to reveal the anti-tumor activity and molecular mechanism of Lycorine and the Chinese medicinal formula that invented in this research. Our results show that both Lycorine and the Chinese medicinal formula that invented in this research possess the ideal inhibition effects on the growth and metastasis of CRPC. Lycorine impairs proliferation of several PCa cell lines through inducing apoptosis and impedes PCa cell migration and invasion through reverting the process of epithelial mesenchymal transitions (EMT). In two animal models, Lycorine suppresses the growth and metastasis of PCa xenografts and improve the survival rate of tumor bearing-mice. Specifically, our study for the first time uncover that Lycorine decreases the downstream signaling pathways of signal transducer and activator of transcription 3 (STAT3) to realize its inhibition in PCa growth and metastasis. Besides, preclinical pharmacological experiments of the Chinese medicinal formula that invented in this research prove that this formula obviously inhibits PCa growth and metastasis through down-regulating the androgen receptor (AR) signaling pathway. It has the bioactivity of not only significantly inhibiting CRPC growth and metastasis, but also considerably improving the survival quality and some typical immune parameters of tumor-bearing mice. Furthermore, this formula exhibits remarkable synergy and attenuation of chemotherapy drugs cyclophosphamide (CTX) activities.To sum up, our results show that both Lycorine and the Chinese medicinal formula that invented in this research inhibit the growth and metastasis of CRPC. Our study provides theoretical and experimental testimony for the further development and clinical application of Lycorine. In addition, our study proves that the Chinese medicinal formula that invented in this research can be exploited as a potential recipe for PCa treatment. In conclusion, our research may supply valuable references for the development of new generation of anti-prostate cancer as well as immunomodulatory drugs from the treasure reserves of TCM resources.