Validity of the Rapid Thyroxine Absorption Test for the Differentiation Between Levothyroxine Non-compliance and Malabsorption in Thyroid-Stimulating Hormone Refractory Hypothyroidism.

Introduction Thyroid-stimulating hormone refractory hypothyroidism is a common problem. This is due to either non-compliance or malabsorption with levothyroxine (LT4). The study aimed to assess the validity of the rapid LT4 absorption test in the differentiation between LT4 malabsorption and non-compliance. Methods A cross-sectional study was done from January to October 2022 at Faiha Specialized Diabetes, Endocrine, and Metabolism Center, in Basrah, Southern Iraq. Twenty-two patients with thyroid-stimulating hormone (TSH) refractory hypothyroidism were evaluated by rapid LT4 absorption test with measurements of TSH before 1000 µg LT4 intake, and free thyroxine (pmol/l) and total thyroxine before (nmol/l) (baseline TT4 and baseline FT4) and two hours after (2-HR TT4 and 2-HR FT4). The findings were compared with the following four-week-long supervised LT4 absorption test results. Results In the rapid LT4 absorption test, patients with (2-HR FT4 minus baseline FT4 ≤1.28 pmol/l (0.1 ng/dl) or 2-HR FT4 minus baseline FT4 1.28-6.43 pmol/l (0.1-0.5 ng/dl) plus 2-HR TT4 minus baseline TT4<72.08 nmol/l (5.6 µg/dl)), eight out of 10 patients were correctly diagnosed with malabsorption. And in those with (2-HR FT4 minus baseline FT4 ≥6.43 (0.5 ng/dl) or 2-HR FT4 minus baseline FT4 1.28-6.43 (0.1-0.5 ng/dl) plus 2-HR TT4 minus baseline TT4≥72.08 (5.6 µg/dl)), 11 out of 12 patients were correctly diagnosed as non-compliant. This criterion showed 88.8% sensitivity, 15.4% specificity, 80% positive predictive value, and 91.6% negative predictive value for diagnosing LT4 malabsorption. Conclusion The rapid LT4 absorption test showed good diagnostic accuracy in differentiating non-compliance from malabsorption when (2-HR FT4 minus baseline FT4) and (2-HR TT4 minus baseline TT4) were used as criteria.

Cannabidiol alters mitochondrial bioenergetics via VDAC1 and triggers cell death in hormone-refractory prostate cancer.

In spite of the huge advancements in both diagnosis and interventions, hormone refractory prostate cancer (HRPC) remains a major hurdle in prostate cancer (PCa). Metabolic reprogramming plays a key role in PCa oncogenesis and resistance. However, the dynamics between metabolism and oncogenesis are not fully understood. Here, we demonstrate that two multi-target natural products, cannabidiol (CBD) and cannabigerol (CBG), suppress HRPC development in the TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model by reprogramming metabolic and oncogenic signaling. Mechanistically, CBD increases glycolytic capacity and inhibits oxidative phosphorylation in enzalutamide-resistant HRPC cells. This action of CBD originates from its effect on metabolic plasticity via modulation of VDAC1 and hexokinase II (HKII) coupling on the outer mitochondrial membrane, which leads to strong shifts of mitochondrial functions and oncogenic signaling pathways. The effect of CBG on enzalutamide-resistant HRPC cells was less pronounced than CBD and only partially attributable to its action on mitochondria. However, when optimally combined, these two cannabinoids exhibited strong anti-tumor effects in TRAMP mice, even when these had become refractory to enzalutamide, thus pointing to their therapeutical potential against PCa.

Prostate cancer metastatic to bilateral testicles: case report and literature review.

PURPOSE: Hormone-refractory prostate cancer (PCa) has a high incidence of metastasis with common secondary site locations. Our case report describes a rare metastatic site of PCa infiltrating bilateral testicles in the absence of definitive radiologic evidence. MATERIALS AND METHODS: Following the patient's consent and IRB exemption, we report the clinical, radiological, and pathological presentation of the patient treated at our institution. We also conducted an inclusive literature review of PCa with bilateral testicular metastases. RESULTS: Our patient is a 54-year-old male who presented to the emergency room with lower urinary tract symptoms and failure to void. A full workup including digital rectal examination, PSA (580 ng/ml), and a transrectal ultrasound (TRUS) biopsy performed afterward revealed an adenocarcinoma of the prostate. The metastatic workup at presentation was negative. After failure to comply with treatment guidelines, the patient was referred back to us with bilateral testicular masses. Without clear evidence of the origin of the masses, bilateral orchiectomy was performed, and pathological analysis confirmed it was metastatic prostate adenocarcinoma. Post-orchiectomy, the patient was again lost to follow up. Three years later the patient returns and placed in palliative care. CONCLUSIONS: This case report highlights that PCa can have a highly variable course and progression can occur in the absence of adherence to treatment. Any evidence of disease relapse and clinical suspicion of metastasis should be investigated, especially in patients with advanced and metastatic disease or poor adherence to surveillance protocol.

Efficacy and tolerability of current treatments for hormone-refractory prostate cancer patients with visceral metastases.

Aim: To assess the efficacy and tolerability of the first-line treatment options for hormone-refractory prostate cancer patients with visceral metastases. Materials & methods: The records of 191 patients diagnosed with hormone-refractory prostate cancer with visceral metastases were analyzed retrospectively. Results: Docetaxel was administered to 61.2% (n = 117), abiraterone to 14.2% (n = 27) and enzalutamide to 9.4% (n = 18) as the first-line treatment. The median survival of the patients receiving docetaxel, abiraterone and enzalutamide as the first-line treatment during the hormone-refractory period was 15 (95% Cl: 12.9-17) months, 6 (95% Cl: 1.8-10.1) months and 11 (95% Cl: 0.9-23.1) months (p = 0.038), respectively. Conclusion: The present study established a statistically significant difference in favor of docetaxel in terms of overall survival and progression-free survival.

Lay abstract The optimal therapeutic option for castration-resistant prostate cancer (CRPC) patients with visceral metastases is unknown. We assessed the efficacy and tolerability of the first-line treatment options for CRPC patients with visceral metastasis. One hundred ninety-one patients diagnosed with CRPC with visceral metastases were included in the study. The present study established a statistically significant difference in favor of docetaxel in terms of overall survival and progression-free survival between first-line docetaxel, abiraterone and enzalutamide treatments in CRPC patients with visceral metastases. For patients who cannot undergo chemotherapy, enzalutamide, among novel androgen pathway inhibitors, may be the most appropriate option, given its numerical, although statistically insignificant, difference in overall survival and its fewer side effects compared with abiraterone.

Radium-223 in the Third-Line Setting in Metastatic Castration-Resistant Prostate Cancer: Impact of Concomitant Use of Enzalutamide on Overall Survival (OS) and Predictors of Improved OS.

INTRODUCTION: Radium-223 (Ra-223) has been recommended for bone-dominant metastatic castration-resistant prostate cancer (mCRPC). Second-generation hormone therapy in combination with Ra-223 in mCRPC has been utilized, yet its benefit has not been well elucidated. We investigated the potential survival benefit of concomitant enzalutamide with Ra-223 in the third-line setting and predictors of improved overall survival (OS). PATIENTS AND METHODS: We retrospectively identified 51 patients with bone-dominant mCRPC that were treated with Ra-223 in the postchemotherapy and post-hormone therapy setting, either alone (group A; n = 32) or with concomitant enzalutamide (group B; n = 19). The primary endpoint was to study the OS difference between groups A and B. The secondary endpoint was to identify predictors of improved OS with Ra-223 in the third-line setting. RESULTS: Mean age was 70.9 years, median baseline prostatic-specific antigen (PSA) was 23.1 ng/mL, alkaline phosphatase was 91 IU/L, and hemoglobin was 12.5 g/dL. There was no difference in median OS between groups A and B, at 20.4 versus 17.5 months, respectively (P = .5186). In univariate and multivariate analyses, only pre-Ra-223 PSA < 30 ng/mL and Eastern Cooperative Oncology Group performance status < 2 were associated with improved OS. CONCLUSION: In our study cohort, concomitant use of enzalutamide with Ra-223 in the mCRPC setting was not associated with improved OS. Only pretreatment PSA < 30 ng/mL and pretreatment Eastern Cooperative Oncology Group performance status < 2 were associated with improved OS. Further prospective studies are warranted.

Oncoxin-Viusid® may improve quality of life and survival in patients with hormone-refractory prostate cancer undergoing onco-specific treatments.

The aim of the present study was to identify the efficacy and safety of Oncoxin-Viusid (OV) as a supportive treatment for patients with prostate cancer (PCA). A prospective, non-randomised, open-label phase II clinical trial, including 25 patients with hormone-refractory PCA (HRPC) was conducted at the Hospital Universitario General Calixto García (Havana, Cuba) between June 2017 and March 2018. Each of the patients received chemotherapy (CTX) and/or radiotherapy (RT) and OV treatment. Patients had a mean age of 73 years, clinical stage IV cancer and a high risk of relapse. Six cycles of CTX were completed by 80% of the patients, adverse reactions decreased and no weight loss was observed. Among the 25 patients, 5 were lost to follow-up and 4 died of disease progression. A total of 16 of these patients survived, of which 15 had an improved quality of life and 10 responded to treatment, with a significant reduction in pain and prostate symptoms and ≥50% reduction in baseline PSA. The progression-free survival (PFS) rate was 59% and the overall survival (OS) rate 64% at 1 year after treatment began. The OV nutritional supplement was effective, leading to a significant improvement in the patients' quality of life, good nutritional status and greater treatment tolerance. A clinical and humoral response was observed, with high survival rates and a delayed appearance of signs of disease progression. The present study was registered in ClinicalTrials.gov PRS with ID #NCT03543670.

Adding carboplatin to chemotherapy regimens for metastatic castrate-resistant prostate cancer in postsecond generation hormone therapy setting: Impact on treatment response and survival outcomes.

BACKGROUND: The clinical course in metastatic castrate-resistant prostate cancer (mCRPC) can be complicated when patients have disease progression after prior treatment with second generation hormone therapy (second HT), such as enzalutamide or abiraterone. Currently, limited data exist regarding the optimal choice of chemotherapy for mCRPC after failing second generation hormone therapy. We sought to evaluate three common chemotherapy regimens in this setting. METHODS: We retrospectively identified 150 mCRPC patients with disease progression on enzalutamide or abiraterone. Of these 150 patients, 92 patients were chemo-naïve while 58 patients had previously received docetaxel chemotherapy before being started on second HT. After failing second HT, 90 patients were assigned for docetaxel-alone (group A), 33 patients received carboplatin plus docetaxel (group B), while 27 patients received cabazitaxel-alone (Group C). A favorable response was defined by more than or equal to 50% reduction in prostate-specific antigen from the baseline level after a complete course of chemotherapy. Survival outcomes were assessed for 30-month overall survival. RESULTS: Patients in group (B) were 2.6 times as likely to have a favorable response compared to patients in group (A) (OR = 2.625, 95%CI: 1.15-5.99) and almost three times compared to patients in group (C) (OR = 2.975, 95%CI: 1.04-8.54) (P = .0442). 30-month overall survival was 70.7%, 38.9% and 30.3% for group (B), (A), and (C), respectively (P = .008). We report a Hazard Ratio of 3.1 (95% CI, 1.31-7.35; P = .0037) between patients in group (A) versus those in group (B) and a Hazard Ratio of 4.18 (95% CI, 1.58-11.06; P = .0037) between patients in group (C) compared to those in group (B) CONCLUSION: This data demonstrates improved response and overall survival in treatment-refractory mCRPC with a chemotherapy regimen of docetaxel plus carboplatin when compared to docetaxel alone or cabazitaxel alone. Further investigations are required.

Prostate Cancer: Biology, Incidence, Detection Methods, Treatment Methods, and Vaccines.

Cancer of the prostate are cancers in which most incidences are slow-growing, and in the U.S., a record of 1.2 million new cases of prostate cancer occurred in 2018. The rates of this type of cancer have been increasing in developing nations. The risk factors for prostate cancer include age, family history, and obesity. It is believed that the rate of prostate cancer is correlated with the Western diet. Various advances in methods of radiotherapy have contributed to lowering morbidity. Therapy for hormone- refractory prostate cancer is making progress, for almost all men with metastases will proceed to hormone-refractory prostate cancer. Smoking cigarettes along with the presence of prostate cancer has been shown to cause a higher risk of mortality in prostate cancer. The serious outcome of incontinence and erectile dysfunction result from the cancer treatment of surgery and radiation, particularly for prostate- specific antigen detected cancers that will not cause morbidity or mortality. Families of patients, as well as patients, are profoundly affected following the diagnosis of prostate cancer. Poor communication between spouses during prostate cancer increases the risk for poor adjustment to prostate cancer. The use of serum prostate-specific antigen to screen for prostate cancer has led to a greater detection, in its early stage, of this cancer. Prostate cancer is the most common malignancy in American men, accounting for more than 29% of all diagnosed cancers and about 13% of all cancer deaths. A shortened course of hormonal therapy with docetaxel following radical prostatectomy (or radiation therapy) for high-risk prostate cancer has been shown to be both safe and feasible. Patients treated with docetaxel-estramustine had a prostate-specific antigen response decline of at least 50%. Cancer vaccines are an immune-based cancer treatment that may provide the promise of a non-toxic but efficacious therapeutic alternative for cancer patients. Further studies will elucidate improved methods of detection and treatment.

Leptomeningeal Metastases in Hormone Refractory Prostate Cancer.

Leptomeningeal metastases from the prostate are extremely rare, with few cases described in the medical literature (antemortem prevalence of less than 0.03%). Prostatic leptomeningeal metastases harbour a poor prognosis with a median survival after diagnosis of 15.7 weeks. We present the case of an 82-year-old male with a history of hormone-refractory prostate cancer who presented to the emergency department with neurological symptoms.

223Ra-chloride therapy in men with hormone-refractory prostate cancer and skeletal metastases: Real-world experience.

BACKGROUND: Radium-223 (223Ra) chloride, an alpha emitter, has been shown to improve overall survival (OS) and pain control, and to delay skeletal-related events, in patients with castration-resistant prostate cancer (CRPC) and bone metastases. Our retrospective observational study presents the first Italian experience on the efficacy and safety of 223Ra therapy in routine clinical practice. METHODS: A total of 83 patients with metastatic CRPC were treated with 223Ra at 3 Italian centers between August 2013 and August 2016. 223Ra-chloride (55 kBq/kg) was administered every 4 weeks for a total of 6 cycles. Primary endpoints were OS and progression-free survival (PFS). Secondary endpoints included toxicity, pain evaluation using numeric rating scale (NRS), symptomatic skeletal-related events and biomarkers response. RESULTS: Patients had a median age of 75 (range 53-89) years. The majority of men showed a Gleason score of 7, 8, or 9. Forty-one patients completed 6 treatment cycles; 33 stopped treatment before completing 6 cycles. Nine were still receiving therapy at the time of data collection. At the end of therapy, NRS pain scores significantly improved ( p < .000001). OS was a mean of 10.1 months, while median OS had not been attained. According to Kaplan-Meier estimation, OS and PFS were 17.5 and 7.7 months, respectively. There was a significant correlation between OS and PFS with the number of 223Ra cycles; patients receiving all 6 cycles experienced the major benefit from the therapy. 223Ra was well-tolerated. CONCLUSIONS: 223Ra alpha therapy is an important therapeutic option for men with CRPC and symptomatic skeletal metastases.

A Systematic Review of Clinical Practice Guidelines for Castration-Resistant Prostate Cancer.

Cancer constitutes a huge burden on societies in countries with any level of economic development. Prostate cancer is the first most diagnosed cancer of men in developed countries and the forth one in developing countries in terms of incidence rate. It is also the third incident cancer of men in Iran along with a prevalence of about 10,000 cases. Castration-resistant prostate cancer (CRPC) is a severe stage of the disease with a number of newly discovered treatment options. These therapeutic alternatives including abiraterone acetate, enzalutamide, cabazitaxel, immunotherapy with sipuleucel-T, radiopharmaceuticals and bone-targeted therapies (zoledronic acid, denosumab) along with docetaxel have made the decision making process complex and challenging for clinicians. In addition to the challenges of selecting the best-fit treatment, high costs of new pharmaceuticals and technologies necessitates the health policy-makers to develop practice guidelines in adaptation with local resources and limitations. The aim of this paper is to review the clinical guidelines for the management of CRPC. For better comprehension of guideline recommendations, the main clinical trials on new treatments were also identified. The efficacy and safety outcomes including but not limited to overall survival, progression free survival, quality of life and adverse effects were summarized. The guidelines of American Urological Association (AUA), National Comprehensive Cancer Network (NCCN), European Association of Urology (EUA), Spanish Oncology Genitourinary Group (SOGG), Asian Oncology Summit, Saudi Oncology Society-Saudi Urology Association combined guideline, National Institute for Health and Care Excellence (NICE) and Canadian Urological Association-Canadian Urologic Oncology Group (CUA-CUOG) were covered in this paper.

Maspin Enhances the Anticancer Activity of Curcumin in Hormone-refractory Prostate Cancer Cells.

BACKGROUND/AIM: Androgen deprivation therapy remains the principal treatment for patients with advanced prostate cancer, though, most patients will eventually develop hormone-refractory prostate cancer (HRPC). Androgen ablation mediated maspin-induction has been identified in cancer patients. However, the role of maspin on the anticancer activity of curcumin derived from turmeric (Curcuma longa) in HRPC cells has not been elucidated. MATERIALS AND METHODS: The anticancer action of curcumin in hormone-independent prostate cancer cells (DU145, and PC-3) was determined by measures of cell survival rate. The cause of maspin silencing on the anti-tumor abilities of curcumin in PC-3 cells was evaluated by measures of cell survival rate, cell-cycle distribution, and apoptosis signaling analysis. RESULTS: Our present study showed that PC-3 cells (with higher maspin expression) were more sensitive than DU145 cells to curcumin treatment (with lower maspin expression). RNA interference-mediated maspin silencing reduced curcumin sensitivity of PC-3 cells, as evidenced by reduced apoptotic cell death. After exposure to curcumin, maspin-knockdown cells showed lower expression levels of pro-apoptotic proteins, Bad and Bax, as compared with control cells. CONCLUSION: Maspin can enhance the sensitivity of HRPC cells to curcumin treatment.

Enantiomerically pure ß-dipeptide derivative induces anticancer activity against human hormone-refractory prostate cancer through both PI3K/Akt-dependent and -independent pathways.

The use of peptides that target cancer cells and induce anticancer activities through various mechanisms is developing as a potential anticancer strategy. KUD983, an enantiomerically pure ß-dipeptide derivative, displays potent activity against hormone-refractory prostate cancer (HRPC) PC-3 and DU145 cells with submicromolar IC50. KUD983 induced G1 arrest of the cell cycle and subsequent apoptosis associated with down-regulation of several related proteins including cyclin D1, cyclin E and Cdk4, and the de-phosphorylation of RB. The levels of nuclear and total c-Myc protein, which could increase the expression of both cyclin D1 and cyclin E, were profoundly inhibited by KUD983. Furthermore, it inhibited PI3K/Akt and mTOR/p70S6K/4E-BP1 pathways, the key signaling in multiple cellular functions. The transient transfection of constitutively active myristylated Akt (myr-Akt) cDNA significantly rescued KUD983-induced caspase activation but did not blunt the inhibition of mTOR/p70S6K/4E-BP1 signaling cascade suggesting the presence of both Akt-dependent and -independent pathways. Moreover, KUD983-induced effect was enhanced with the down-regulation of anti-apoptotic Bcl-2 members (e.g., Bcl-2, and Mcl-1) and IAP family members (e.g., survivin). Notably, KUD983 induced autophagic cell death using confocal microscopic examination, tracking the level of conversion of LC3-I to LC3-II and flow cytometric detection of acidic vesicular organelles-positive cells. In conclusion, the data suggest that KUD983 is an anticancer ß-dipeptide against HRPCs through the inhibition of cell proliferation and induction of apoptotic and autophagic cell death. The suppression of signaling pathways regulated by c-Myc, PI3K/Akt and mTOR/p70S6K/4E-BP1 and the collaboration with down-regulation of Mcl-1 and survivin may explain KUD983-induced anti-HRPC mechanism.

Efficacy and safety of post-docetaxel therapies in metastatic castration-resistant prostate cancer: a systematic review of the literature.

OBJECTIVE: Prostate cancer is a highly prevalent form of cancer in older men and is one of the leading causes of death from cancer in men across the globe. Many therapeutic agents have been approved for patients with metastatic castration-resistant prostate cancer (mCRPC), particularly as a post-docetaxel treatment strategy. The objective of this systematic literature review was to assess published efficacy and safety data for select mCRPC therapies - such as abiraterone, cabazitaxel, and enzalutamide - in the post-docetaxel setting. METHODS: Database searches of MEDLINE, Embase, and Cochrane CENTRAL, in conjunction with hand searches of multiple congress abstracts, yielded 13 randomized studies and 107 non-randomized studies that met the inclusion criteria. RESULTS: Randomized studies demonstrated significant improvements in median overall survival (OS) outcomes over placebo for abiraterone (15.8 vs. 11.2 months) and enzalutamide (18.4 vs. 13.6 months), and similar significant improvements were noted for cabazitaxel over mitoxantrone (15.1 vs. 12.7 months). Differences in progression-free survival (PFS) were similarly significant, although variance in the criteria for measuring PFS may limit the extent to which these outcomes can be compared between studies. Non-randomized evidence included multiple publications from several early access and compassionate use programs with a primary objective to report safety outcomes. Results from these studies largely reflected the findings in randomized trials. CONCLUSIONS: Overall, there is a growing body of evidence for post-docetaxel treatment options available in patients with mCRPC. Further head-to-head trials or indirect treatment comparisons may be a valuable method to assess the comparative efficacy of these therapies.

[Hormone Resistance and Neuroendocrine Differentiation Due to Accumulation of Genetic Lesions during Clonal Evolution of Prostate Cancer].

Progression of malignant tumors is largely due to clonal evolution of the primary tumor, clones acquiring different sets of molecular genetic lesions. Lesions can confer a selective advantage in proliferation rate or metastasis on the tumor cell population, especially if developing resistance to anticancer therapy. Prostate cancer (PCa) provides an illustrative example of clinically significant clonal evolution. The review considers the genetic alterations that occur in primary PCa and the mechanism whereby hormone-refractory PCa develops on hormone therapy, including mutations and alternative splicing of the androgen receptor gene (AR) and intratumoral androgen synthesis. Certain molecular genetic lesions determine resistance to new generation inhibitors (AR mutations that block the antagonist effect or allow other hormones to activate the receptor) or lead to neuroendocrine differentiation (repression of the AR signaling pathway, TP53 mutations, and amplification of the AURKA or MYCN oncogene). Multistep therapy based on the data about somatic mutations associated with progression and metastasis of the primary tumor can be expected to significantly improve the survival of patients with advanced PCa in the nearest future.

Case Studies in the Management of Metastatic Breast Cancer with Eribulin.

Outcomes for triple-negative or hormone-refractory metastatic breast cancer (MBC) are poor and treatment options are limited. Described herein are cases of two women who developed MBC following adjuvant chemotherapy and endocrine therapy for human epidermal growth factor receptor 2 (HER2)-negative ductal carcinoma. Both underwent treatment with fulvestrant, followed by paclitaxel and letrozole or nab-paclitaxel. Following disease progression, both patients started single-agent eribulin mesylate (1.4 mg/m(2) on Days 1 and 8 of a 21-day cycle). The first patient is currently continuing on eribulin at full dose, despite interruption for hip surgery and the presence of grade 1 neuropathy in the hands and feet. The second patient had a partial response with eribulin, which was sustained for 4 months. She was able to tolerate the full dose of eribulin despite slight worsening of the neuropathy that was present at baseline. Eribulin may be a beneficial option for hormone-refractory MBC with extensive treatment experience.

Biological effects of novel "combi-targeting" molecule and its effect on DNA repair pathway in hormone-refractory prostate cancer.

OBJECTIVE: This study aimed to investigate the biological effects of "combi-targeting" JDF12 and its effect on the DNA repair pathway in hormone-refractory prostate cancer (HRPC). METHODS: HRPC cell lines (PC3 cells and VCap cells) were treated with JDF12 at different concentrations, and SRB method was employed to detect the proliferation of HRPC cells; Annexin V-FITC kit was used to detect the apoptosis of PC3 cells; Alkaline comet assay was performed to detect DNA damage; Western blot assay was done to detect the expressions of autophosphorylated EGFR, XRCC1 and ERCC1 (later two are proteins in DNA repair pathway); the anti-tumor effect was evaluated in nude mice inoculated with PC3 cells. RESULTS: JDF12 could inhibit the proliferation of PC3 cells and VCap cells in a concentration dependent manner (IC50: 14.04 ± 1.22 for PC3 and 15.57 ± 1.13 for VCap) and significantly increase the apoptotic cells as compared to those treated with mitozolomide or iressa alone. In PC3 cells, JDF12 induced DNA damage and also inhibited the expressions of phosphorylated EGFR, XRCC1 and ERCC1 in a concentration dependent manner. Moreover, JDF12 markedly inhibited tumor growth in nude mice. CONCLUSION: The novel "combi-targeting" JDF12 may exert more potent anti-proliferative effect as compared to mitozolomide or iressa alone, and the inhibitory effect on the EGFR signaling pathway and down-regulated XRCC1 and ERCC1 expressions may be ascribed to the JDF12 induced DNA damage.

Zerumbone, a ginger sesquiterpene, induces apoptosis and autophagy in human hormone-refractory prostate cancers through tubulin binding and crosstalk between endoplasmic reticulum stress and mitochondrial insult.

Zerumbone, a natural monocyclic sesquiterpene, is the main component of the tropical plant Zingiber zerumbet Smith. Zerumbone induced antiproliferative and apoptotic effects against PC-3 and DU-145, two human hormone-refractory prostate cancer (HRPC) cell lines. Zerumbone inhibited microtubule assembly and induced an increase of MPM-2 expression (specific recognition of mitotic proteins). It also caused an increase of phosphorylation of Bcl-2 and Bcl-xL, two key events in tubulin-binding effect, indicating tubulin-binding capability and mitotic arrest to zerumbone action. Furthermore, zerumbone induced several cellular effects distinct from tubulin-binding properties. First, zerumbone significantly increased, while paclitaxel (as a tubulin-binding control) decreased, Mcl-1 protein expression. Second, paclitaxel but not zerumbone induced Cdk1 activity. Third, zerumbone other than paclitaxel induced Cdc25C downregulation. The data suggest that, in addition to targeting tubulin/microtubule, zerumbone may act on other targets for signaling transduction. Zerumbone induced mitochondrial damage and endoplasmic reticulum (ER) stress as evidenced by the loss of mitochondrial membrane potential and upregulation of GRP-78 and CHOP/GADD153 expression. Zerumbone induced an increase of intracellular Ca(2+) levels, a crosstalk marker between ER stress and mitochondrial insult, associated with the formation of active calpain I fragment. It induced apoptosis through a caspase-dependent way and caused autophagy as evidenced by dramatic LC3-II formation. In summary, the data suggest that zerumbone is a multiple targeting compound that inhibits tubulin assembly and induces a crosstalk between ER stress and mitochondrial insult, leading to apoptosis and autophagy in HRPCs.

Lycorine is a novel inhibitor of the growth and metastasis of hormone-refractory prostate cancer.

Lycorine, a natural alkaloid extracted from the Amaryllidaceae plant family, has been reported to exhibit a wide range of physiological effects, including the potential effect against cancer. However, the anti-prostate cancer (PCa) efficacy of Lycorine remains unrevealed. In this context, we figured out Lycorine's anti-proliferative and anti-migratory properties for PCa treatment. Lycorine inhibited proliferation of various PCa cell lines, induced cell apoptosis and cell death. Here we showed that Lycorine decreased proliferation, migration, invasion, survival and EMT of prostate cancer cell lines. Subcutaneous and orthotopic xenotransplantations by ectopic implantation of the human hormone-refractory PC-3M-luc cells were used to confirm in vivo anticancer effects of Lycorine. Lycorine inhibited both growth and metastasis in multiple organs (liver, lung, kidney, spleen and bone) in vivo and improved mice survival. Lycorine prevented EGF-induced JAK/STAT signaling. Importantly, anti-cancer effects of Lycorine were dependent on STAT expression. We suggest that Lycorine is a potential therapeutic in prostate cancer.