Prostate Growth Research Articles

Docking and Molecular Dynamics Identify Leads against 5 Alpha Reductase 2 for Benign Prostate Hyperplasia Treatment

Steroid 5 alpha-reductase 2 (5αR-2) is a membrane-embedded protein that together with other isoforms plays a key role in the metabolism of steroids. This enzyme catalyzes the reduction of testosterone to the more potent ligand, dihydrotestosterone (DHT) in the prostate. Androgens, testosterone, and DHT play important roles in prostate growth, development, and function. At the same time, both testosterone and DHT have been implicated in the pathogenesis of benign prostate hyperplasia (BPH). Inhibition of the DHT formation, therefore, provides a therapeutic strategy that offers the possibility of preventing, delaying, or treating BPH. Currently, two steroidal drugs that inhibit 5αR-2, dutasteride and finasteride, have been approved for clinical use. These two come at a high cost and also portray undesirable sexual side effects which necessitate the need to find new chemotherapeutic alternatives for the disease. Based on the aforementioned, finasteride and dutasteride were subjected to scaffold hopping, fragment-based de novo design, molecular docking, and molecular dynamics simulations employing databases like ChEMBL, DrugBank, PubChem, ChemSpider, and Zinc15 in the identification of potential hits targeting 5αR-2. Altogether, ten novel compounds targeting 5αR-2 were identified with binding energies lower or comparable to finasteride and dutasteride, the main inhibitors for this target. Molecular docking and molecular dynamics simulations studies identify amino acid residues Glu57, Phe219, Phe223, and Leu224 to be critical for ligand binding and complex stability. The physicochemical and pharmacological profiling suggests the potential of the hit compounds to be drug-like and orally active. Similarly, the quality parameter assessments revealed the hits possess LELP greater than 3 implying their promise as lead-like molecules. The compounds A5, A9, and A10 were, respectively, predicted to treat prostate disorders with Pa (0.188, 0.361, and 0.270) and Pi (0.176, 0.050, and 0.093), while A8 and A9 were found to be associated with BPH treatment with Pa (0.09 and 0.127) and Pi (0.077 and 0.033), respectively. Structural similarity searches via DrugBank identified the drugs faropenem, acemetacin, estradiol valerate, and yohimbine to be useful for BPH treatment suggesting the de novo designed ligands as potential chemotherapeutic agents for treating this disease.

Dietary Soybean may be Antiestrogenic in Male Mice

We tested whether dietary soybeans alter prostatic growth and development of prostatic dysplasia in mice that were treated with a synthetic nonsteroidal estrogen, diethylstilbestrol during the first 3 d after birth. Soybeans were chosen because they contain substantial amounts of isoflavonic estrogens. The presence of estrogenic isoflavonoids in soybean-containing feed was confirmed by measuring the excretion of seven different plant estrogens in the urine of normal adult male mice. Estrogenicity of dietary soybean was confirmed by the growth response in uteruses of immature mice. In addition to their estrogenic effect, antiestrogenic properties of soybeans on uterine growth were observed in the presence of a more potent estrogenic growth stimulator, diethylstilbestrol in feed. In neonatally estrogenized male mice, soybean feeding reduced the prostatic growth inhibition due to diethylstilbestrol and, in preliminary experiments, delayed the development of dysplastic changes in the prostate. The number of animals showing severe dysplasia in prostatic epithelium was significantly lower in 9-mo-old animals given soybean-containing feed from fertilization onwards, but in 12 mo-old animals the difference was less obvious and was not significant. Our findings suggest an antiestrogenic action for dietary soybean in male mice, which may be important for the hormonal regulation of normal as well as neoplastic prostatic growth.

Efficacy of 1-Year Cavacurmin® Therapy in Reducing Prostate Growth in Men Suffering from Lower Urinary Tract Symptoms

We aim to assess the effect of Cavacurmin® on prostate volume (PV), lower urinary tract symptoms (LUTS) and micturition parameters in men after 1 year of therapy. From September 2020 to October 2021, data from 20 men with LUTS/benign prostatic hyperplasia and PV ≥40 mL who were on therapy with α1-adrenoceptor antagonists plus Cavacurmin® were retrospectively compared with 20 men on only α1-adrenoceptor antagonists. Patients were evaluated at baseline and after 1 year using the International Prostate Symptom Score (IPSS), prostate-specific antigen (PSA), maximum urinary flow (Qmax) and PV. A Mann-Whitney U-test and Chi-square were used to assess the difference between the two groups. A comparison of paired data was performed with the Wilcoxon signed-rank test. Statistical significance was set at p-value < 0.05. There was no statistically significant difference in baseline characteristics between the two groups. At the 1-year follow-up, PV [55.0 (15.0) vs. 62.5 (18.0) mL, p = 0.04)], PSA [2.5 (1.5) ng/mL vs. 3.05 (2.7) vs. p = 0.009] and IPSS [13.5 (3.75) vs. 18 (9.25) p = 0.009] were significantly lower in the Cavacurmin® group. Qmax was significantly higher in the Cavacurmin® group [15.85 (2.9) vs. 14.5 (4.2), p = 0.022]. PV was reduced to 2 (5.75) mL in the Cavacurmin® group from baseline, while it increased to 12 (6.75) mL in the α1-adrenoceptor antagonists group (p < 0.001). PSA decreased in the Cavacurmin® group [-0.45 (0.55) ng/mL], whereas it increased in the α1-adrenoceptor antagonists group [0.5 (0.30) ng/mL, p < 0.001]. In conclusion, one-year Cavacurmin® therapy was able to block prostate growth with a concomitant decrease in PSA value from baseline. The association of Cavacurmin® with α1-adrenoceptor antagonists had a more beneficial effect compared to patients on α1-adrenoceptor antagonists alone but this needs further larger studies to be confirmed, particularly in the long-term.

Hexane-extracted saw palmetto (Permixon®) inhibits prostate stromal cell proliferation and growth, and disrupts actin formation

Hexane-extracted saw palmetto (Permixon®) inhibits prostate stromal cell proliferation and growth, and disrupts actin formation

Immunohistochemistry analysis of estrogen receptor and androgen receptor in benign prostatic hyperplasia and prostate carcinoma

Benign prostatic hyperplasia (BPH) and prostate adenocarcinoma are the most common disorders affecting elderly men. The diseases are androgen-dependent and are treated by obstructing androgen receptor (AR) or their action. AR has direct relationship between the development of prostatic hyperplasia and prostatic carcinoma. Estrogens directly target prostate tissue by definite estrogen receptors (ER). The human prostate is primed with a dual system of ERs (ER-α and ER-β). Use of estrogens as hormonal agents is for suppressing prostatic tissue growth. Study aims to identify, assess and establish the significance of ER and AR as a marker in distinguishing BPH and prostatic carcinoma. A cross sectional study was conducted at a tertiary care hospital over a period of two year on 65 specimens which included 30 malignant cases and 35 benign cases. Specimens received were tru-cut biopsy, transurethral resection of prostate chips (TURP) and prostatectomy specimen for malignant cases and TURP for benign lesions. Paraffin embedded blocks was stained with H&amp;E and IHC with ER and AR performed on representative sections and graded .the results were assessed for association with various parameters in both benign and malignant cases. Out of 30 cases of adenocarcinoma of prostate majority of specimens were needle biopsies (54%). The age of presentation was 55-84 years with mean age being 68.93 years. In cases of BPH the presenting age was 35-84 years and mean age was 63 years. Histopathological parameters assessed for malignant lesions, showed negative correlation of grade group with PNI and positive correlation with neutrophils. Higher grade showed adverse histological parameters. %PSA was &amp;#60;25% in malignancy. ER positivity was noted in 80% malignant and 100% benign cases with weaker positivity noted maximum in benign cases. AR positivity was noted in all cases both benign and malignant, with benign cases showing higher intensity. Hormones play a multifactorial role in the pathogenesis of BPH and prostatic carcinoma; most commonly androgen and estrogen, and can be used towards finding a better therapy.

Age, weight and circulating concentrations of total testosterone are associated with the relative prostatic size in adult intact male dogs

Prostatic hyperplasia (PH) is an androgen-dependent condition associated with increased prostatic size that is common in intact dogs, and similar to the condition in men. In dogs, the increase in prostatic size is most prominent the first years, and after approximately four years (in beagles), a plateau is reached, and further growth is slower. Why the prostate continues to grow more in some individuals is not clear. Most testosterone in the circulation is bound to albumin or sex hormone binding globulin (SHBG) and only a minor part is unbound and biologically active. The binding to SHBG has higher affinity than that to albumin. In addition, SHBG has own biological functions, modifying testosterone action. The aim of the present study was to investigate if there is an association between relative prostatic size and the variables total testosterone concentration, SHBG concentration, an estimation of bioavailable testosterone: the ratio between testosterone and SHBG (free androgen index, FAI), estradiol concentration, the estradiol/testosterone ratio, dog age and dog weight. Hormone concentrations were measured in serum from 79 intact male dogs aged ≥ four years, weighing ≥ five kg. The size of the prostate was estimated using ultrasonography, and relative prostate size, Srel, was calculated as the estimated size related to the normal size for a 4-year-old dog of the same weight. There as a negative correlation between testosterone concentration and age (ρ = −0.27, P = 0.018) and a positive correlation between age and Srel (ρ = 0.27, P = 0.016) and between SHBG and weight (ρ = 0.38, P = 0.001). The FAI was negatively correlated with dog weight (ρ = −0.32, P = 0.004). There were no significant correlations between Srel and SHBG or FAI or between estradiol or estradiol/testosterone and Srel, age or weight. A multiple regression analysis showed significant associations between log Srel and log testosterone concentration, log age and log weight of the dog, with an adjusted R2 of 9.5%. Although the variables total testosterone concentration, age and weight of the dog were all significantly associated with Srel, the coefficient of determination was low, indicating that they only explained a minor part of the prostatic size. The results support the analysis of total testosterone in studies of prostatic growth in the dog.

To β or Not to β: How Important Is β-Catenin Dependent and Independent WNT Signaling in CLL?

WNT pathways play an important role in cancer development and progression, but WNT pathways can also inhibit growth in melanoma, prostate, and ovarian cancers. Chronic lymphocytic leukemia (CLL) is known for its overexpression of several WNT ligands and receptors. Canonical WNT signaling is β-catenin-dependent, whereas non-canonical WNT signaling is β-catenin-independent. Research on WNT in CLL focuses mainly on non-canonical signaling due to the high expression of the WNT-5a receptor ROR1. However, it was also shown that mutations in canonical WNT pathway genes can lead to WNT activation in CLL. The focus of this review is β-catenin-independent signaling and β-catenin-dependent signaling within CLL cells and the role of WNT in the leukemic microenvironment. The major role of WNT pathways in CLL pathogenesis also makes WNT a possible therapeutic target, directly or in combination with other drugs.

Relative Influence of Ageratum conyzoides L. Plant Extracts on Testosterone Induced Benign Prostatic Hyperplasia in Mice

Pharmacognosy Research,2023,15,1,75-83.DOI:10.5530/097484900266Published:December 2022Type:Original ArticleAuthors:Tongchen Jomba, and Manuj Kumar Bharali Author(s) affiliations:Tongchen Jomba1, Manuj Kumar Bharali1,2,* 1Cell and Molecular Biology Section, Department of Zoology, Rajiv Gandhi University, Rono Hills, Doimukh, Arunachal Pradesh, INDIA. 2Cell and Molecular Biology Section, Department of Zoology, Gauhati University, Guwahati, Assam, INDIA. Abstract:Purpose: The present study was designed to investigate the inhibitory efficacy of aqueous and ethanolic extracts of Ageratum conyzoide L. (AC, Family asteraceae) on testosterone induced BPH in male mice. Materials and Methods: Mice were randomly divided into five groups (n=6): negative control group received corn oil, BPH model group receive testosterone (5mg/kg/day, S.C) dissolved in corn oil. Another group received standard BPH drug finasteride (5 mg/Kg/day, I.P) along with testosterone injection (5mg/kg/day, S.C). The other two group of animals received either aqueous or ethanolic AC plant extracts (100, 500. 1000 and 2000 mg/kg, I.P) along with testosterone (5mg/kg/day, S.C) consecutively for 28 days. All animals were sacrificed at the end of the study period and prostate weight and prostatic index were determined, followed by histolopathological examination of the prostate gland. Results: The result of the present study indicated that treatment with either plant extracts caused significant reduction in prostate weight and prostatic index when compared to only testosterone treated animal group. The percentage of inhibition of prostate growth was found to be correlated in a dose dependent manner in plant extract treated groups. Histopathological examination of prostate gland revealed AC plant extracts treatment significantly reduced the glandular hyperplasia, epithelial thickness and stromal hyperplasia in the prostate gland of the treated animals. No significant elevation in serum ALT and creatinine level was recorded in any groups during the study period. Conclusion: This study hence indicate the therapeutic potential in Ageratum conyzoides L. plant extract in testosterone induced BPH model in mice. Keywords:Ageratum conyzoides, Benign prostatic hyperplasia, Inhibition, Plant extracts, Prostate, TestosteroneView:PDF (608.09 KB)

Relationship Between Transabdominal Measurements of Prostate Volume and Anthropometric Measurements among Male Residents in Ondo State

Introduction: The prostate gland is a major site of diseases like prostatitis, benign prostatic hyperplasia and carcinoma of the prostate. Growth and enlargement of prostate can be predicted by prostate volume in the future. The prostate gland volume are influenced by a number of factors which includes age, body mass index (BMI), waist circumference (WC) and ethnicity. Aim: To study the relationship between anthropometric measurements and transabdominal measurements of prostate volume among male Residents in Ondo State. Method: A cross-sectional descriptive study was carried out at Ultrasound Department, University of Medical Sciences Teaching Hospital, Ondo, Ondo state with 200 healthy adults categorized into 4 age groups 1,2,3 and 4 i.e 20-50 years, 51-60 years, 61-70years, &gt;71 years. Three categories of BMI was formed which are Healthy (18 to 25 kg/m2), Overweight (&gt;25 to 29 kg/m2), Obese (≥30 kg/m2). Data analysis was done using SPSS version 20. Post hoc- LSD Fishers test was applied to make comparison between means of different groups. Univariate analysis was used to test the linear association among the variables. . P-value &lt; 0.05 was considered significant. Results: Mean age of the subject in this study was 46.3 ± 17.0 years (Table 1). Age group was divided into group 1, 2, 3 and 4 i.e 20-50 years, 51-60 years, 61-70years, &gt;71 years with 125, 29, 24 and 22 subjects respectively (Table 2). The BMI was classified into three groups which includes normal weight, over weight and obese with 100, 65 and 35 subjects respectively. The mean BMI in the study was 25.8 ± 4.61. Significant positive correlation was seen between prostrate volume and Age and positively with BMI. The correlation coefficients were (r=0.017) and (r=0.062) respectively. Conclusion: Age plays a significant role in the determination of prostate volume. The prostrate volume increases as the age increases. Also BMI has a contributing factor to change in prostate volume as the Obese people have an increase prostate volume.

The Emergence of Cancer Stem Cells in Early Diagnosed Prostate Cancer

The Emergence of Cancer Stem Cells in Early Diagnosed Prostate Cancer

SC139 - Synergistic effects of curcumin and lactoferrin to inhibit the prostatic cancer cells growth and migration ability

SC139 - Synergistic effects of curcumin and lactoferrin to inhibit the prostatic cancer cells growth and migration ability

P48 - Synergistic effects of curcumin and lactoferrin to inhibit the prostatic cancer cells growth and migration ability

P48 - Synergistic effects of curcumin and lactoferrin to inhibit the prostatic cancer cells growth and migration ability

WNT1 Inducible Signaling Pathway Protein 1 Is a Stroma-Specific Secreting Protein Inducing a Fibroblast Contraction and Carcinoma Cell Growth in the Human Prostate.

The WNT1 inducible signaling pathway protein 1 (WISP1), a member of the connective tissue growth factor family, plays a crucial role in several important cellular functions in a highly tissue-specific manner. Results of a RT-qPCR indicated that WISP1 expressed only in cells of the human prostate fibroblasts, HPrF and WPMY-1, but not the prostate carcinoma cells in vitro. Two major isoforms (WISP1v1 and WISP1v2) were identified in the HPrF cells determined by RT-PCR and immunoblot assays. The knock-down of a WISP1 blocked cell proliferation and contraction, while treating respectively with the conditioned medium from the ectopic WISP1v1- and WISPv2-overexpressed 293T cells enhanced the migration of HPrF cells. The TNFα induced WISP1 secretion and cell contraction while the knock-down of WISP1 attenuated these effects, although TNFα did not affect the proliferation of the HPrF cells. The ectopic overexpression of WISP1v1 but not WISP1v2 downregulated the N-myc downstream regulated 1 (NDRG1) while upregulating N-cadherin, slug, snail, and vimentin gene expressions which induced not only the cell proliferation and invasion in vitro but also tumor growth of prostate carcinoma cells in vivo. The results confirmed that WISP1 is a stroma-specific secreting protein, enhancing the cell migration and contraction of prostate fibroblasts, as well as the proliferation, invasion, and tumor growth of prostate carcinoma cells.

Bmal1 Regulates Prostate Growth via Cell-Cycle Modulation.

The circadian clock system exists in most organs and regulates diverse physiological processes, including growth. Here, we used a prostate-specific Bmal1-knockout mouse model (pBmal1 KO: PbsnCre+; Bmal1fx/fx) and immortalized human prostate cells (RWPE-1 and WPMY-1) to elucidate the role of the peripheral prostate clock on prostate growth. Bmal1 KO resulted in significantly decreased ventral and dorsolateral lobes with less Ki-67-positive epithelial cells than the controls. Next, the cap analysis of gene expression revealed that genes associated with cell cycles were differentially expressed in the pBmal1 KO prostate. Cdkn1a (coding p21) was diurnally expressed in the control mouse prostate, a rhythm which was disturbed in pBmal1 KO. Meanwhile, the knockdown of BMAL1 in epithelial RWPE-1 and stromal WPMY-1 cell lines decreased proliferation. Furthermore, RWPE-1 BMAL1 knockdown increased G0/G1-phase cell numbers but reduced S-phase numbers. These findings indicate that core clock gene Bmal1 is involved in prostate growth via the modulation of the cell cycle and provide a rationale for further research to link the pathogenesis of benign prostatic hyperplasia or cancer with the circadian clock.

First-in-Class Small Molecule to Inhibit CYP11A1 and Steroid Hormone Biosynthesis.

Binding of steroid hormones to their cognate receptors regulates the growth of most prostate and breast cancers. We hypothesized that CYP11A inhibition might halt the synthesis of all steroid hormones, because CYP11A is the only enzyme that catalyses the first step of steroid hormone biosynthesis. We speculated that a CYP11A inhibitor could be administered safely provided that the steroids essential for life are replaced. Virtual screening and systematic structure-activity relationship optimization were used to develop ODM-208, the first-in-class, selective, nonsteroidal, oral CYP11A1 inhibitor. Safety of ODM-208 was assessed in rats and Beagle dogs, and efficacy in a VCaP castration-resistant prostate cancer (CRPC) xenograft mouse model, in mice and dogs, and in six patients with metastatic CRPC. Blood steroid hormone concentrations were measured using liquid chromatography-mass spectrometry. ODM-208 binds to CYP11A1 and inhibited its enzymatic activity. ODM-208 administration led to rapid, complete, durable, and reversible inhibition of the steroid hormone biosynthesis in an adrenocortical carcinoma cell model in vitro, in adult noncastrated male mice and dogs, and in patients with CRPC. All measured serum steroid hormone concentrations reached undetectable levels within a few weeks from the start of ODM-208 administration. ODM-208 was well tolerated with steroid hormone replacement. The toxicity findings were considered related to CYP11A1 inhibition and were reversed after stopping of the compound administration. Steroid hormone biosynthesis can be effectively inhibited with a small-molecule inhibitor of CYP11A1. The findings suggest that administration of ODM-208 is feasible with concomitant corticosteroid replacement therapy.

Vitamin D receptor polymorphism and prostate cancer prognosis.

Prostatic epithelial cells synthesize the active form of vitamin D (1,25-dihydroxyvitamin D3), which participates in regulating prostate growth. Calcitriol, a synthetic form of vitamin D3, exhibits antiproliferative and prodifferentiation activities in prostate cancer. The function of 1,25-dihydroxyvitamin D3 is mediated by its binding to vitamin D receptor (VDR). VDR forms a heterodimer, typically with retinoid X receptor, to regulate vitamin D target genes. We evaluated the relationship between VDR polymorphism and clinical characteristics associated with prostate cancer risk and prognosis among Egyptian men. This case-control study included 2 groups of patients: group A, a control group of 50 subjects with benign prostate hyperplasia, and group B, 50 subjects newly diagnosed with prostate cancer. All participants performed complete blood count, liver and kidney function tests, prostate specific antigen measurement, histopathological analysis and immunohistochemistry for Dickkopf Homolog 3. Restriction fragment length polymorphism-polymerase chain reaction as performed to detect VDR polymorphism. Patients with prostate cancer and controls showed a significantly different CA genotype frequency (p = 0.007). Furthermore, prostate-specific antigen levels were significantly different in different genotypes in patients with prostate cancer (p < 0.001). Finally, T stage and the VDR ApaI C/A polymorphism were significantly associated (p < 0.041). The VDR ApaI C/A polymorphism may be a diagnostic and prognostic marker for prostate cancer in Egyptian men.

New generation biomarkers for the detection of prostate cancer

Malignant growth is the most dangerous illness with the most elevated mortality rate. Early identification of malignant growth can be fundamental in effective treatment. One of the most promising early symptomatic tools for tracking infection spread and subsequent disease treatment is biomarker-based malignant growth screening. Prostate cancer (PCa) is the most widely recognized reason for death in men and is the following driving reason for death from the disease worldwide. Prostate-specific antigen (PSA) is a fundamental biomarker for diagnosing PCa. Despite signs against its utilization in massive populace tests, PSA concentrates most on PCa biomarkers. This biomarker does remain an essential determinant in the therapy of prostate malignant growth due to its different structures and its inclusion in rehashed plans with other biomarkers. This paper depicts the most recent advances in electrochemical biosensors intended to identify different malignant growth biomarkers utilizing further sign transmission and biological detection strategies. In treating malignant prostate growth, disclosing its specific structures and inclusion in revised schemes with other biomarkers are crucial indicators.

Low Doses of PFOA Promote Prostate and Breast Cancer Cells Growth through Different Pathways.

Endocrine Disrupting Compounds (EDCs) are found in everyday products. Widely distributed throughout the environment, persistent organic pollutants (POPs) are a specific class of EDCs that can accumulate in adipose tissue. Many of them induce adverse effects on human health—such as obesity, fertility disorders and cancers—by perturbing hormone effects. We previously identified many compounds with EDC activity in the circulation of obese patients who underwent bariatric surgery. Herein, we analyzed the effects of four of them (aldrin, BDE28, PFOA and PCB153) on two cancer cell lines of hormone-sensitive organs (prostate and breast). Each cell line was exposed to serial dilutions of EDCs from 10−6 M to 10−12 M; cytotoxicity and proliferation were monitored using the IncuCyte® technology. We showed that none of these EDCs induce cytotoxicity and that PFOA and PCB153, only at very low doses (10−12 M), increase the proliferation of DU145 (prostate cancer) and MCF7 (breast cancer) cells, while the same effects are observed with high concentrations (10−6 M) for aldrin or BDE28. Regarding the mechanistic aspects, PFOA uses two different signaling pathways between the two lines (the Akt/mTORC1 and PlexinD1 in MCF7 and DU145, respectively). Thus, our study demonstrates that even at picomolar (10−12 M) concentrations PFOA and PCB153 increase the proliferation of prostate and breast cancer cell lines and can be considered possible carcinogens.

Glucocorticoids are induced while dihydrotestosterone levels are suppressed in 5-alpha reductase inhibitor treated human benign prostate hyperplasia patients.

The development of benign prostatic hyperplasia (BPH) and medication-refractory lower urinary tract symptoms (LUTS) remain poorly understood. This study attempted to characterize the pathways associated with failure of medical therapy for BPH/LUTS. Transitional zone tissue levels of cholesterol and steroids were measured in patients who failed medical therapy for BPH/LUTS and controls. Prostatic gene expression was measured using qPCR and BPH cells were used in organoid culture to study prostatic branching. BPH patients on 5-α-reductase inhibitor (5ARI) showed low levels of tissue dihydrotestosterone(DHT), increased levels of steroid 5-α-reductase type II (SRD5A2), and diminished levels of androgen receptor (AR) target genes, prostate-specific antigen (PSA), and transmembrane serine protease 2 (TMPRSS2). 5ARI raised prostatic tissue levels of glucocorticoids (GC), whereas alpha-adrenergic receptor antagonists (α-blockers) did not. Nuclear localization of GR in prostatic epithelium and stroma appeared in all patient samples. Treatment of four BPH organoid cell lines with dexamethasone, a synthetic GC, resulted in budding and branching. After failure of medical therapy for BPH/LUTS, 5ARI therapy continued to inhibit androgenesis but a 5ARI-induced pathway increased tissue levels of GC not seen in patients on α-blockers. GC stimulation of organoids indicated that the GC receptors are a trigger for controlling growth of prostate glands. A 5ARI-induced pathway revealed GC activation can serve as a master regulator of prostatic branching and growth.

Abstract 4044: An extract of olive oil wastewater enhances chemotherapy effects on breast cancer cells without exacerbating cardiovascular toxicity

Abstract Background: In cancer patients receiving chemotherapeutic agents, cardiovascular toxicities still remains one of the most undesirable side effects. One of the best known cardiotoxic agents is doxorubicin, a very powerful chemotherapeutic molecules for breast cancer. Extra-virgin olive oil (EVOO) is rich in cancer preventive polyphenols endowed with anti-inflammatory, anti-oxidant activities which could exert protective effects on heart cells. A very interesting derivative of EVOO preparation is represented by purified extracts from olive mill waste waters (OMWW) rich in polyphenols. Here, we have investigated the anti-cancer activity of a OMWW preparation, named A009, on breast cancer cells when combined with chemotherapeutics, as well as its potential cardioprotective activities. We had previously reported additive effects with cisplatin in prostate cancer cells. In previous studies we have shown that the combination of A009 with cisplatin or 5-FU was effective in decreasing prostate and colon cancer cell growth, while it did not further reduce growth of rat cardiomyocytes also treated with cisplatin or 5-FU. Here we used 5-fluorouracil as comparison. Methods: Combination of A009 and chemotherapy was investigated in vitro on human breast cancer cell lines BT459, MDA-MB-234. The cardioprotective effects of the A009 extract were tested on H9C2 (cardiomyocytes) cells co-exposed to doxorubicin or 5-fluorouracil and in zebrafish embryos. Results: Adding A009 to doxorubicin or 5-FU was effective in decreasing breast cancer cell growth in monolayer. Breast tumor spheroids morphologically appeared less stable and with reduced diameter when treated with A009 extracts and with the chemotherapeutic agents 5-FU or Doxo, additive effects were observed. A009 mitigated toxicity of doxorubicin or 5-FU on rat cardiomyocytes cells H9C2. Cardioprotective effects were observed by the combination of OMWW extracts with Doxorubicin in Zebrafish embryos. In human cardiomyocytes, we observed 5-FU induced upregulation of the proinflammatory IL6 mRNA, which was reduced by OMWW treatment. Conclusions: Our study demonstrates that the polyphenol rich purified A009 extracts enhance the effect of chemotherapy of doxorubicin and 5-FU on breast cancer cells but mitigates chemotherapy adverse effects on heart in vivo and on cardiomyocytes, appearing as a potential cardio-oncological prevenzion agent. Citation Format: Adriana Albini, Marco M. Festa, Denisa Baci, Nadia Benedetto, Karolina Gutmanska, Nicoletta Macrì, Giovanna Finzi, Fausto Sessa, Serena Zacchigna, Antonino Bruno, Douglas M. Noonan. An extract of olive oil wastewater enhances chemotherapy effects on breast cancer cells without exacerbating cardiovascular toxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4044.