Oral administration of E-type prostanoid (EP) 1 receptor antagonist suppresses carcinogenesis and development of prostate cancer via upregulation of apoptosis in an animal model

doi:10.21203/rs.3.rs-800415/v1

Download PDF

Research Article

Oral administration of E-type prostanoid (EP) 1 receptor antagonist suppresses carcinogenesis and development of prostate cancer via upregulation of apoptosis in an animal model

https://doi.org/10.21203/rs.3.rs-800415/v1

This work is licensed under a CC BY 4.0 License

You are reading this latest preprint version

Prostaglandin E2 plays important roles in carcinogenesis and malignant potential of prostate cancer (PC) by binding to its specific receptors, E-type prostanoid (EP) receptors. However, anti-carcinogenic effects of EP receptor antagonist are not clear. In this study, feed with or without EP1 receptor antagonist were given to a mouse model of prostate cancer. The mice were sacrificed at 10, 15, 30, and 52 weeks of age. Apoptosis was evaluated by immunohistochemical analysis using cleaved caspase-3. The incidence of cancer in the experimental group was significantly lower than that in the control group at 15, 30, and 52 weeks of age. The percentage of poorly differentiated PC cells was significantly lower in the experimental group than in the control group at 30 and 52 weeks of age. The survival period in the experimental group was significantly longer than that in the control group, and the percentage of apoptotic cells in the experimental group was significantly higher than that in the control group at 15, 30, and 52 weeks of age. Thus, an EP1 receptor antagonist delayed PC progression via the upregulation of apoptosis. We suggest that EP1 receptor may be a novel chemopreventive agent for the development of PC.

Cancer Biology

Oncology

Urology & Nephrology

group

receptor

weeks

experimental

significantly

Prostate cancer (PC) is the most common malignancy in men. Various treatments, such as surgery, hormonal therapy, chemotherapy, and radiotherapy, are performed for PC patients according to their clinicopathological features and background^1–3. In addition, the clinical usefulness of active surveillance has been reported in selected patients with favorable- and intermediate-risk PC^3,4. Conservative treatments, including active surveillance, can avoid adverse events, maintain quality of life, and save the patient from further medical treatments. Thus, information on suppression methods of malignant potential and tumor growth is important to discuss the treatment strategies aimed at both improving prognosis and maintaining quality of life in patients with PC.

Prostaglandin E2 (PGE2) is a strong mediator of various pathological conditions including cancers^5,6. Cyclooxygenase (COX)-2 plays crucial roles in the metabolism of arachidonic acid to PGE2. Therefore, COX-2 is well known to be positively associated with carcinogenesis, malignant aggressiveness, and poor outcomes in many types of malignancies^7–9. However, pathological activities of PGE2 are not always dependent on COX-2 because various other factors besides COX-2 regulate PGE2 production^10,11. Briefly, although COX-2 inhibitors, including non-steroid anti-inflammatory drugs, are reported to act as tumor suppressors via regulation of PGE2 in many types of cancers^12,13, COX-2 inhibitors may inhibit some of the pathological activities of PGE2. On the other hand, we should know the facts that the binding of PGE2 to its specific receptor, E-prostanoid receptor (EP), is essential to exsert pathophysiological functions of PGE2 [14]. The EP receptor family consists of four isoforms (EP1–4 receptor), and the interactions between PGE2 and EP receptors in malignancies vary depending on cell type and tumor-surrounding conditions^5,7,15,16.

Regarding the PGE2 / EP receptor axes in PC, many investigators have suggested that they play important pathological roles in malignant potential and tumor growth^16–20. However, the detailed pathological significance of each EP receptor in PC tissues is not fully understood. In addition, there is little information on the efficacy and safety of chemopreventive and treatment strategies using anti-EP receptor agents in PC by in vivo studies. In a previous study, we showed that EP1, EP2, and EP4 receptors play crucial roles in carcinogenesis in patients with hormone-sensitive PC¹⁷. In addition, EP1 receptor expression was shown to be positively associated with tumor grade and TNM stage¹⁷. Based on these results, we hypothesized that blocking of the EP1 receptor leads to suppression of carcinogenesis and tumor growth in PC in vivo. The main aim of this study was to test this hypothesis using a PC mouse model that showed close-to-human kinetics of tumor development. In addition, the influence of the EP1 receptor agonist on apoptosis in PC cells in the same mouse tissues was assessed.

Animals. The knock-in mouse adenocarcinoma prostate (KIMAP) model was used in this study. This model has previously been used to evaluate the pathological roles of cancer-related factors and anti-cancer effects of various foods in PC because pathological characteristics and tumor progression kinetics of PC in KIMAP are known to be similar to those in human PC^21–23. The detailed information on rearing environment, anesthesia, and welfare is described in our previous reports^22,24. All animal experiments were performed according to the Guidelines for Animal Experiments of Nagasaki University, and the protocol was approved by the Regulations of Animal Care and Use Committee of Nagasaki University. We confirmed that this study is reported in accordance with ARRIVE guidelines.

Food preparation. The EP1 receptor agonist was orally administered through a feed containing ONO-8713, which is a selective antagonist for the EP1 receptor (provided by ONO Pharmaceuticals, Osaka, Japan). In the experimental group, ONO-8713 was mixed with standard feed (AIN-76A, CLEA Japan, Inc., Tokyo, Japan) (final concentration of 1,00 ppm), according to a previous report²⁵. Feed with EP1 receptor antagonist was administered from 8 weeks of age, and we confirmed that the reduced amounts of feed were similar between the control and experimental groups every week.

Tissue collection and analyses. Mice were sacrificed and tissues were collected at 10, 15, 30, and 52 weeks of age. Hematoxylin and eosin (H&E) staining was performed on the collected tissues for histological examination. A schematic of the study protocol is shown in Figure 1. The apoptotic index (AI) was calculated by anti-cleaved caspase-3 (Asp 175) (R&D Systems, Minneapolis, MN) according to our previous report^22,26.

Statistical analyses.

All data were expressed as median and interquartile range (IQR). The Mann-Whitney U test was used to compare continuous variables. Kaplan-Meier survival curves and the log-rank test were performed for survival analysis. A significance was defined as p < 0.05. All statistical analyses were performed by statistical package StatView for Windows (Version 5.0, Abacus Concept, Berkeley, CA).

Changes of histological characteristics. PC cells were not detected in either group at 10 weeks of age. At 15 weeks of age, cancer cells were relatively rare in the experimental group (Fig. 2A); however, carcinogenic changes in the prostate glands were found in the control group (Fig. 2B). In fact, the median/IQR of the percentage of cancer cells in the experimental group (11.0/9.7–12.2%) was significantly lower (p<0.001) than in the control group (50.7/49.4–51.6%). At 30 weeks of age, cancer tissues and normal prostate glands were mixed in the experimental group (Fig. 2C); however, PC tissues with glandular structures were found in the control group (Fig. 2D). Furthermore, at 52 weeks of age, the area of cancer tissues was increased in the experimental group, although glandular PC tissues and normal glands still existed (Fig. 2E). In contrast, in the control group, undifferentiated cancer cells clearly appeared at 52 weeks of age (Fig. 2F).

Frequency of cancer cells. The changes in the percentage of cancer cells in the experimental and control groups are shown in Figure. 3A. The frequencies of cancer cells in experimental group was significantly lower compared to control group at 15, 30 and 52 weeks of age. On the other hand, as shown in Fig. 3B, there were no significant differences in poorly differentiated PC cells between the groups at 10 and 15 weeks of age. However, the percentage of poorly differentiated PC cells was significantly lower (p<0.001) in the experimental group (2.7/1.8–3.4% and 49.9/47.5–52.7%) than in the control group (19.6/19.2–22.1% and 98.4/97.3–100.0%) at 30 and 52 weeks of age, respectively (Fig. 3B). Thus, at 52 weeks of age, although almost all cancer cells were judged as poorly differentiated in the control group, the frequency of poorly differentiated PC cells in the experimental group was nearly half that of cancer cells.

Survival analyses and safety. In the control group, 2 of 15 mice (11.1%) died before 30 weeks of age, and 4 of 15 mice (26.7%) died from 31 to 52 weeks of age. In contrast, only one mouse (6.7%) died at 43 weeks of age in the experimental group. There was no injury, bite, or infection in any of the mice, including dead mice. Kaplan-Meier survival curves showed that the survival period in the experimental group was significantly longer than that in the control group (Fig. 4, p=0.043). There was no significant difference in body weight or food intake between the control and experimental groups.

Change of frequency of apoptotic cells. As shown in Fig. 5, at 15 weeks of age, AI in the experimental group (2.8/2.5–3.3 %) was significantly higher (p=0.040) than that in the control group (2.2/1.8–2.8). In addition, a similar significant difference was found at 30 and 52 weeks of age (p=0.040 and 0.038, respectively; Fig. 5).

The present study demonstrated that the EP 1 receptor antagonist delayed carcinogenesis and tumor growth in a PC animal model. Many investigators have suggested that COX-2 inhibitors are useful for the chemoprevention and treatment of malignancies in preclinical studies and clinical trials^27–29. However, it should be noted that the addition of COX-2 inhibitor did not significantly affect the outcomes of randomized clinical trials of non-small cell lung cancer and colon cancer patients^30,31. In PC, several in vivo and in vitro studies showed that anti-cancer effects including improvement of prognosis of COX-2 inhibitors were limited^32–35. Thus, the chemopreventive and anti-cancer effects of COX-2 inhibitors in PC are still controversial. On the other hand, there is the opinion that comprehensive regulation of PGE2 production by systematic administration of COX-2 inhibitors is speculated to lead to weakness of anti-cancer effects and increased risk of adverse events due to global prostanoid suppression³⁶. In fact, COX-2 inhibitors are known to upregulate the risk of various visceral disorders, such as gastrointestinal and cardiovascular toxicities^37–39. In addition, other investigators have suggested that inhibition of the EP receptor pathway is a more effective approach for improving the anti-cancer effects compared to treatment strategies using COX-2 inhibitors⁴⁰. Based on these facts, we believe that more specific inhibition of PGE2 activity is necessary to improve the efficacy and safety of chemoprevention and treatment of PC patients.

Regarding expression pattern and pathological roles of EP receptors in PC, in vitro studies showed that EP2 and EP4 receptors were expressed in PC-3 cells and in PC-3, DU145, LNCaP, and PrEC cells, respectively⁴¹. Other in vitro studies have also shown that EP2 and EP4 receptors are mainly expressed in PC cell lines, and overexpression of EP2 and EP4 receptors and reduced EP3 expression were observed in PC tissues^18,19. Thus, these reports showed that the pathological significance of the EP1 receptor was minimal in PC. However, interestingly, inhibition of EP1 receptor signaling led to the suppression of proliferation in PC cell lines⁴². In addition, in an animal model, EP1 receptor-positive PC cells play a crucial role in cancer cell proliferation²⁰. Moreover, in human PC tissues, EP1 receptor expression is significantly associated with Gleason score, TNM stage, and cancer cell proliferation¹⁷. Although there was no general agreement on the pathological roles of the EP1 receptor in PC, we selected the EP1 receptor agonist according to the results obtained in PC cell lines, animal experiments, and human tissues.

The usefulness of treatment strategies by agonists of each EP receptor has been reported in various types of malignancies; for example, the EP1 and EP2 receptors for breast cancer^43,44, EP3 receptor for oral cancer⁴⁵, and EP4 receptor for lung cancer and breast cancer^40,^46,47. On the other hand, regarding PC, the EP1 receptor antagonist (SC51322) showed anti-proliferative effects on cancer cells, whereas the EP2, EP3, and EP4 receptor antagonists did not⁴². Unfortunately, there is little information on the pro-apoptotic activity of EP1 receptor inhibitor in PC cells. However, oral intake of an EP1 antagonist was reported to have chemopreventive effects via stimulation of apoptosis without any side effects in a breast cancer animal model⁴³. These previous findings support our results on chemopreventive effects, stimulative function of apoptosis, and safety of EP1 antagonist.

A limitation of this study is that the chemopreventive effects of other EP receptor antagonists have not been investigated. In addition to the EP1 receptor, in vitro and animal experiments have shown that the EP4 receptor is a potential therapeutic target for PC⁴⁸. Furthermore, we previously reported that EP2 receptor- and EP3 receptor-expressing cancer stromal cells were positively associated with cancer cell progression and worse outcomes in patients with PC¹⁶. Thus, it is possible that EP2–EP4 agonists may have chemopreventive and anti-cancer effects in in vivo studies. In recent years, a combination therapy of anti-PD-L1 antibody and EP4 antagonist enhanced anti-tumor growth effects and prolonged survival in mice inoculated with murine lymphoma cells⁴⁹. Finally, we suggest further in vivo studies, including animal experiments, to discuss the usefulness, limitations, and safety of novel therapeutic strategies by inhibition of EP receptor pathways and of combined therapies with such treatments and other conventional therapies in PC.

Our in vivo study using KIMAP demonstrated that an EP1 receptor antagonist delayed carcinogenesis and prolonged survival periods. Induction of apoptosis was speculated to be associated with such chemopreventive effects. There was no toxicity, including pathological findings in the kidney and liver. Finally, we concluded that inhibition of the EP1 receptor pathway by an EP1 antagonist is a novel chemopreventive strategy for PC.

Acknowledgements

We thank Dr. Keiji Wakabayashi and Dr. Michihiro Mutoh in National Cancer Center for their advice on making the experimental feed.

Author contributions

Y.Miyata, M.M., K.M., A.A., Y.N., K.A., Y. Mukae, T.Matsuda, J.H., T. Matsuo, K.O. and H.S. had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Y. Miyata. Acquisition of data: M.M., K.M., A.A., Y.N., K.A., Y. Mukae, T.Matsuda, J.H., T. Matsuo, K.O. Analysis and interpretation of data: Y. Miyata, A.A., Y.N. Drafing of the manuscript: Y.Miyata, M.M. Statistical analysis: Y.Miyata. Study supervision: H.S.

Funding

This study was supported by JPSS KAKENHI (grant number: 16K11012).

Competing interests

The authors declare that they have no conflict of interest

Agrawal, V., Ma, X., Hu, J. C., Barbieri, C. E. & Nagar, H. Active Surveillance for Men with Intermediate Risk Prostate Cancer. J. Urol, 205, 115–121 (2021).
Ambati, G. G. & Jachak, S. M. Natural Product Inhibitors of Cyclooxygenase (COX) Enzyme: A Review on Current Status and Future Perspectives. Curr. Med. Chem, 28, 1877–1905 (2021).
Arora, M., Choudhary, S., Singh, P. K., Sapra, B. & Silakari, O. Structural investigation on the selective COX-2 inhibitors mediated cardiotoxicity: A review. Life Sci, 251, 117631 (2020).
Bernichtein, S. et al. High milk consumption does not affect prostate tumor progression in two mouse models of benign and neoplastic lesions. PLoS One, 10, e0125423 (2015).
Bi, N. et al. Effect of Concurrent Chemoradiation With Celecoxib vs Concurrent Chemoradiation Alone on Survival Among Patients With Non-Small Cell Lung Cancer With and Without Cyclooxygenase 2 Genetic Variants: A Phase 2 Randomized Clinical Trial. JAMA Netw Open, 2, e1918070 (2019).
Bieniek, J., Childress, C., Swatski, M. D. & Yang, W. COX-2 inhibitors arrest prostate cancer cell cycle progression by down-regulation of kinetochore/centromere proteins., 74, 999–1011 (2014).
Cervantes-Madrid, D. L. & Nagi, S. & Asting Gustafsson, A. FosB transcription factor regulates COX-2 expression in colorectal cancer cells without affecting PGE2 expression. Oncol. Lett, 13, 1411–1416 (2017).
Chen, Y. & Hughes-Fulford, M. Prostaglandin E2 and the protein kinase A pathway mediate arachidonic acid induction of c-fos in human prostate cancer cells. Br. J. Cancer, 82, 2000–2006 (2000).
Cheuk, I. W. et al. Association of EP2 receptor and SLC19A3 in regulating breast c cancer metastasis. Am. J. Cancer Res, 5, 3389–3399 (2015).
Finetti, F. et al. Prostaglandin E2 and Cancer: Insight into Tumor Progression and Immunity.Biology (Basel)9 (2020).
Flamiatos, J. F. et al. Cyclooxygenase-2 (COX-2) inhibition for prostate cancer chemoprevention: double-blind randomised study of pre-prostatectomy celecoxib or placebo. BJU Int, 119, 709–716 (2017).
Gabril, M. Y. et al. A novel knock-in prostate cancer model demonstrates biology similar to that of human prostate cancer and suitable for preclinical studies. Mol. Ther, 11, 348–362 (2005).
Goncalves, R. M. et al. COX-2 promotes mammary adipose tissue inflammation, local estrogen biosynthesis, and carcinogenesis in high-sugar/fat diet treated mice. Cancer Lett, 502, 44–57 (2021).
He, P., Yang, C., Ye, G., Xie, H. & Zhong, W. Risks of colorectal neoplasms and cardiovascular thromboembolic events after the combined use of selective COX-2 inhibitors and aspirin with 5-year follow-up: a meta-analysis. Colorectal Dis, 21, 417–426 (2019).
Hoshikawa, H., Goto, R., Mori, T., Mitani, T. & Mori, N. Expression of prostaglandin E2 receptors in oral squamous cell carcinomas and growth inhibitory effects of an EP3 selective antagonist, ONO-AE3-240. Int. J. Oncol, 34, 847–852 (2009).
Huang, H. F. et al. Significance of divergent expression of prostaglandin EP4 and EP3 receptors in human prostate cancer. Mol. Cancer Res, 11, 427–439 (2013).
Kawamori, T. et al. Chemopreventive effects of ONO-8711, a selective prostaglandin E receptor EP(1) antagonist, on breast cancer development., 22, 2001–2004 (2001).
Kim, J. I., Lakshmikanthan, V., Frilot, N. & Daaka, Y. Prostaglandin E2 promotes lung cancer cell migration via EP4-betaArrestin1-c-Src signalsome. Mol. Cancer Res, 8, 569–577 (2010).
Lage, D. E. et al. Outcomes of older men receiving docetaxel for metastatic hormone-sensitive prostate cancer.Prostate Cancer Prostatic Dis.(2021).
Lee, J. S., Kim, H. S., Hahm, K. B. & Surh, Y. J. Effects of Genetic and Pharmacologic Inhibition of COX-2 on Colitis-associated Carcinogenesis in Mice. J Cancer Prev, 25, 27–37 (2020).
Ma, X., Kundu, N., Rifat, S., Walser, T. & Fulton, A. M. Prostaglandin E receptor EP4 antagonism inhibits breast cancer metastasis. Cancer Res, 66, 2923–2927 (2006).
Makita, H. et al. A prostaglandin E2 receptor subtype EP1-selective antagonist, ONO-8711, suppresses 4-nitroquinoline 1-oxide-induced rat tongue carcinogenesis., 28, 677–684 (2007).
Marra, G. et al. Long-term Outcomes of Focal Cryotherapy for Low- to Intermediate-risk Prostate Cancer: Results and Matched Pair Analysis with Active Surveillance.Eur Urol Focus(2021).
Matsuo, T. et al. Green Tea Polyphenol Induces Changes in Cancer-Related Factors in an Animal Model of Bladder Cancer. PLoS One, 12, e0171091 (2017).
Meyerhardt, J. A. et al. Effect of Celecoxib vs Placebo Added to Standard Adjuvant Therapy on Disease-Free Survival Among Patients With Stage III Colon Cancer: The CALGB/SWOG 80702 (Alliance) Randomized Clinical Trial. JAMA, 325, 1277–1286 (2021).
Miyata, Y. et al. Relationship between prostaglandin E2 receptors and clinicopathologic features in human prostate cancer tissue. Urology, 68, 1360–1365 (2006).
Miyata, Y., Kanda, S., Nomata, K., Eguchi, J. & Kanetake, H. Expression of cyclooxygenase-2 and EP4 receptor in transitional cell carcinoma of the upper urinary tract. J. Urol, 173, 56–60 (2005).
Miyata, Y. et al. Pathological function of prostaglandin E2 receptors in transitional cell carcinoma of the upper urinary tract. Virchows Arch, 448, 822–829 (2006).
Miyata, Y. et al. Tumor-associated stromal cells expressing E-prostanoid 2 or 3 receptors in prostate cancer: correlation with tumor aggressiveness and outcome by angiogenesis and lymphangiogenesis. Urology, 81, 136–142 (2013).
Miyata, Y. et al. Pathological significance and predictive value for biochemical recurrence of c-Fes expression in prostate cancer., 72, 201–208 (2012).
Mizuno, R., Kawada, K. & Sakai, Y. Prostaglandin E2/EP Signaling in the Tumor Microenvironment of Colorectal Cancer.Int. J. Mol. Sci.20 (2019).
Mohammadi, A. et al. HSP90 Inhibition Suppresses PGE2 Production via Modulating COX-2 and 15-PGDH Expression in HT-29 Colorectal Cancer Cells. Inflammation, 39, 1116–1123 (2016).
Nakai, Y. et al. Biochemical control of the combination of cyclooxygenase-2 inhibitor and (125) I-brachytherapy for prostate cancer: Post hoc analysis of an open-label controlled randomized trial. Int. J. Urol, 27, 755–759 (2020).
Norel, X. et al. International Union of Basic and Clinical Pharmacology. CIX. Differences and Similarities between Human and Rodent Prostaglandin E2 Receptors (EP1-4) and Prostacyclin Receptor (IP): Specific Roles in Pathophysiologic Conditions. Pharmacol. Rev, 72, 910–968 (2020).
Ogino, S. et al. Cyclooxygenase-2 expression is an independent predictor of poor prognosis in colon cancer. Clin. Cancer Res, 14, 8221–8227 (2008).
Ruan, D. & So, S. P. Prostaglandin E2 produced by inducible COX-2 and mPGES-1 promoting cancer cell proliferation in vitro and in vivo. Life Sci, 116, 43–50 (2014).
Sajiki, Y. et al. Enhanced Immunotherapeutic Efficacy of Anti-PD-L1 Antibody in Combination with an EP4 Antagonist. Immunohorizons, 4, 837–850 (2020).
Sheng, J. et al. The Role of Cyclooxygenase-2 in Colorectal Cancer. Int. J. Med. Sci, 17, 1095–1101 (2020).
Smyth, L. et al. Statin and cyclooxygenase-2 inhibitors improve survival in newly diagnosed diffuse large B-cell lymphoma: a large population-based study of 4913 subjects. Br. J. Haematol, 191, 396–404 (2020).
Sooriakumaran, P. & Kaba, R. The risks and benefits of cyclo-oxygenase-2 inhibitors in prostate cancer: a review. Int. J. Surg, 3, 278–285 (2005).
Teo, M. Y., Rathkopf, D. E. & Kantoff, P. Treatment of Advanced Prostate Cancer. Annu. Rev. Med, 70, 479–499 (2019).
Terada, N. et al. Identification of EP4 as a potential target for the treatment of castration-resistant prostate cancer using a novel xenograft model. Cancer Res, 70, 1606–1615 (2010).
Wagner, M. et al. Resistance of prostate cancer cell lines to COX-2 inhibitor treatment. Biochem. Biophys. Res. Commun, 332, 800–807 (2005).
Wang, X. & Klein, R. D. Prostaglandin E2 induces vascular endothelial growth factor secretion in prostate cancer cells through EP2 receptor-mediated cAMP pathway. Mol. Carcinog, 46, 912–923 (2007).
Watanabe, S. et al. Expression of X-linked inhibitor of apoptosis protein in human prostate cancer specimens with and without neo-adjuvant hormonal therapy. J. Cancer Res. Clin. Oncol, 136, 787–793 (2010).
Xin, X. et al. Targeting COX-2 and EP4 to control tumor growth, angiogenesis, lymphangiogenesis and metastasis to the lungs and lymph nodes in a breast cancer model. Lab. Invest, 92, 1115–1128 (2012).
Xu, D., Cai, J., Wan, Z. K., Gao, H. & Sun, Y. Pathophysiological role of prostaglandin E synthases in liver diseases. Prostaglandins Other Lipid Mediat, 154, 106552 (2021).
Yeh, C. C. et al. Metronomic Celecoxib Therapy in Clinically Available Dosage Ablates Hepatocellular Carcinoma via Suppressing Cell Invasion, Growth, and Stemness in Pre-Clinical Models. Front. Oncol, 10, 572861 (2020).
Zeng, Y. et al. Inhibition of prostate carcinogenesis in probasin/SV40 T antigen transgenic rats by raloxifene, an antiestrogen with anti-androgen action, but not nimesulide, a selective cyclooxygenase-2 inhibitor., 26, 1109–1116 (2005).

No competing interests reported.

Download PDF

Editorial decision: Major revision
01 Sep, 2021
Reviews received at journal
17 Aug, 2021
Reviewers agreed at journal
14 Aug, 2021
Reviewers invited by journal
12 Aug, 2021
Editor assigned by journal
12 Aug, 2021
Editor invited by journal
12 Aug, 2021
Submission checks completed at journal
12 Aug, 2021
First submitted to journal
11 Aug, 2021

You are reading this latest preprint version

Oral administration of E-type prostanoid (EP) 1 receptor antagonist suppresses carcinogenesis and development of prostate cancer via upregulation of apoptosis in an animal model

Status:

Version 1

Abstract

Figures

Introduction

Materials And Methods

Results

Discussion

Conclusion

Declarations

References

Additional Declarations

Status:

Version 1