Synthesis and evaluation of a novel near-infrared fluorescent probe based on succinimidyl-Cys-C(O)-Glu that targets prostate-specific membrane antigen for optical imaging

Prostate-specific membrane antigen (PSMA), which is highly expressed in both localized and metastatic prostate cancer (PCa), is an ideal target for imaging and therapy of PCa. We previously reported radiolabeled asymmetric urea derivatives as a PSMA-targeting radiotracer for single-photon emission computed tomography (SPECT) and positron emission tomography (PET) imaging. Here, based on these radiopharmaceutical probes, we designed a novel near-infrared (NIR) fluorescent imaging probe (800CW-SCE) by chemical conjugation between IRDye 800CW-Maleimide and an asymmetric urea compound, known as PSMA inhibitor, for optical imaging. In the in vitro cellular uptake study, 800CW-SCE was internalized into PSMA-positive PCa cells (LNCaP cells) but not into PSMA-negative PCa cells (PC-3 cells). Moreover, in the in vivo imaging study, the probe was highly accumulated in LNCaP tumors but not in PC-3 tumors, and remained in LNCaP tumors until 24 h after intravenous administration. These results suggest that the potent NIR conjugate may contribute to clinical intraoperative optical imaging.     

Hyperfixations costales bifocales découvertes à la TEP au fluorure (18F) de sodium lors de la stadification d’un cancer de la prostate

A prostate biopsy screening (PSA = 2 ng/mL) evidenced a prostate adenocarcinoma featuring a Gleason score of 8 (4 + 4) in a 62-year-old patient incurring an increased familial risk of prostate cancer. In order to stage the prostate adenocarcinoma, 2 PET scans were ordered. A PET/CT examination with FNa disclosed two hot spots on distinct ribs matching with heterogeneous sclerotic areas on low dose CT. A PET/CT examination with FDG disclosed a hypermetabolic focus of prostate left lobe and a weak intensity hypermetabolic focus of left ilio-obturator node but no bone metabolic abnormality. Staging was categorized distant (bone) metastatic disease upon FNa PET/CT findings. The patient benefited from pelvic external beam radiation therapy and hormone therapy. One year later, a PET/CT examination with FCH while patient was still on hormone therapy depicted a photopaenic area of prostate left lobe and a questionable hypermetabolic focus of right lobe but no bone metabolic abnormality. Retrospectively, bone lesions visible on PET with FNa were already conspicuous on plain X-rays and a CT examination performed a decade before. A new advice in a center specialized in bone and joint imaging suggested a benign condition for these protracted rib lesions even if the exact benign condition was elusive (fibrous dysplasia, aneurysmal bone cyst…). Two years later, the patient is symptom-free and his PSA level is 0.03 ng/mL.     

Estimating bias in causes of death ascertainment in the Finnish Randomized Study of Screening for Prostate Cancer

BackgroundPrecise cause of death (CoD) ascertainment is crucial in any cancer screening trial to avoid bias from misclassification due to excessive recording of diagnosed cancer as a CoD in death certificates instead of non-cancer disease that actually caused death. We estimated whether there was bias in CoD determination between screening (SA) and control arms (CA) in a population-based prostate cancer (PCa) screening trial.MethodsOur trial is the largest component of the European Randomized Study of Screening for Prostate Cancer with more than 80,000 men. Randomly selected deaths in men with PCa (N = 442/2568 cases, 17.2%) were reviewed by an independent CoD committee. Median follow-up was 16.8 years in both arms.ResultsOverdiagnosis of PCa was present in the SA as the risk ratio for PCa incidence was 1.19 (95% confidence interval (CI) 1.14–1.24). The hazard ratio (HR) for PCa mortality was 0.94 (95%CI 0.82–1.08) in favor of the SA. Agreement with official CoD registry was 94.6% (κ = 0.88) in the SA and 95.4% (κ = 0.91) in the CA. Altogether 14 PCa deaths were estimated as false-positive in both arms and exclusion of these resulted in HR 0.92 (95% CI 0.80–1.06).ConclusionsA small differential misclassification bias in ascertainment of CoD was present, most likely due to attribution bias (overdiagnosis in the SA). Maximum precision in CoD ascertainment can only be achieved with independent review of all deaths in the diseased population. However, this is cumbersome and expensive and may provide little benefit compared to random sampling.     

Selecting proper combination of mpMRI sequences for prostate cancer classification using multi-input convolutional neuronal network

PurposeThis study aims to develop a deep-learning-based method to classify clinically significant (CS) and clinically insignificant (CiS) prostate cancer (PCa) on multiparametric magnetic resonance imaging (mpMRI) automatically, and to select suitable mpMRI sequences for PCa classification in different anatomic zones.MethodsA multi-input selection network (MISN) is proposed for both PCa classification and the selection of the optimal combination of sequences for PCa classification in a specific zone. MISN is a multi-input/-output classification network consisting of nine branches to process nine input images from the mpMRI data. To improve classification accuracy and reduce model parameters, a pruning strategy is proposed to select a subset of the nine branches of MIST to form two more effective networks for the peripheral zone (PZ) PCa and transition zone (TZ) PCa, which are named as PZN and TZN, respectively. Besides, a new penalized cross-entropy loss function is adopted to train the networks to balance the classification sensitivity and specificity.ResultsThe proposed methods were evaluated on the PROSTATEx challenge dataset and achieved an area under the receiver operator characteristics curve of 0.95, which was much higher than currently published results and ranked first out of more than 1500 entries submitted to the challenge at the time of submission of this paper. For PZ-PCa and TZ-PCa classification, PZN and TZN achieved better performance than MISN.ConclusionsHigher performance can be achieved by selecting a suitable subset of the mpMRI sequences in PCa classification.     

Hiperparatiroidismo secundario en el cáncer de próstata avanzado

Background and ObjectiveHigh parathyroid hormone (PTH) concentrations are associated with increased bone resorption and bone matrix degradation. Some studies show elevated PTH concentrations and hypocalcemia in patients with advanced prostate carcinoma, although the pathophysiological significance of these findings is not well defined.Materials and methodsWe performed a retrospective study of 60 patients diagnosed with advanced prostate cancer (44 nonmetastatic and 16 metastatic) treated with androgen deprivation. In all patients, PTH, calcium, phosphorus, 25 (OH) vitamin D and prostate-specific antigen (PSA) were determined. Bone scintigraphy had previously been performed.ResultsIn patients with bone metastases, mean concentrations were as follows: calcium 9.19 mg/dl, phosphorus 3.47 mg/dl, 25 (OH) vitamin D 13.85 ng/ml, PTH 66.8 pg/ml and total PSA 101.27 ng/ml. For those without bone metastases, the results were calcium 9.39 mg/dl, phosphorus 3.38 mg/dl, 25 (OH) vitamin D 20.50 ng/ml, PTH 52.23 pg/ml and total PSA 2.52 ng/ml. PTH levels were significantly higher in patients with prostate cancer and bone metastases than in those without metastases (p=0.03). Vitamin D levels were also significantly lower in this group (p=0.03). There were no differences in other values.ConclusionsThe present study found increased PTH concentrations in patients with advanced prostate cancer. This finding could be useful to predict disease progression.     

Use of choline tracers in the prostate carcinoma management

Prostate cancer is the second most frequently diagnosed cancer in men. This incidence has increased because of the introduction of screening with prostate-specific antigen (PSA) and the use of improved biopsy techniques. Choline PET/CT cannot be recommended as a first-line screening procedure for primary prostate cancer. PET/CT has a limited sensitivity due to its dependency on tumor configuration and size, and a limited specificity in differentiation between prostate cancer and benign pathologies. PET/CT could be useful in the detection of malignant lymph nodes in case of nodes greater than 5 mm in diameter. An application of choline PET/CT may be to increase the detection rate of clinically suspected prostate cancer with multiple negative prostate biopsies. Choline PET/CT has proved to be useful for restaging patients with prostate cancer with biochemical failure. Studies have shown that the positive detection rate of choline PET/CT increases with increasing PSA values. The definition of a PSA cut-off value to refer prostate carcinoma with biochemical recurrence would be helpful for the clinical management of these patients. Several PSA cut-off values have been proposed by literature. The routine use of choline PET/CT cannot be recommended only in patients with an absolute PSA value of < 1 ng/mL. Moreover, the sensitivity of ¹⁸F-Fluorocholine (FCH) PET/CT is significantly higher in patients with a PSA velocity > 2 ng/mL per year or a PSA-doubling time ≤ 6 months. In case of early bone metastases ¹⁸F-FCH could be superior to ¹⁸F-sodium fluoride due to the absence of bone reaction and remodelling.     

Hypoxia induced CA9 inhibitory targeting by two different sulfonamide derivatives including Acetazolamide in human Glioblastoma

HIF-1α regulated genes are mainly responsible for tumour resistance to radiation- and chemo-therapy. Among these genes, carbonic anhydrase isoform IX (CA9) is highly over expressed in many types of cancer especially in high grade brain cancer like Glioblastoma (GBM). Inhibition of the enzymatic activity by application of specific chemical CA9 inhibitor sulphonamides (CAI) like Acetazolamide (Aza.), the new sulfonamide derivative carbonic anhydrase inhibitor (SU.D2) or indirect inhibitors like the HIF-1α inhibitor Chetomin or molecular inhibitors like CA9-siRNA are leading to an inhibition of the functional role of CA9 during tumorigenesis. Human GBM cells were treated with in vitro hypoxia (1, 6, or 24 h at 0.1%, O₂). Aza. application was at a range between 250 and 8000 nM and the HIF-1α inhibitor Chetomin at a concentration range of 150–500 nM. Cell culture plates were incubated for 24 h under hypoxia (0.1% O₂). Further, CA9-siRNA constructs were transiently transfected into GBM cells exposed to extreme hypoxic aeration conditions. CA9 protein expression level was detectable in a cell-type specific manner under normoxic conditions. Whereas U87-MG exhibited a strong aerobic expression, U251 and U373 displayed moderate and GaMG very weak normoxic CA9 protein bands. Aza. as well as SU.D2 displayed inhibitory characteristics to hypoxia induced CA9 expression in the four GBM cell lines for 24 h of hypoxia (0.1% O₂) at concentrations between 3500 and 8000 nM, on both the protein and mRNA level. Parallel experiments using CA9-siRNA confirmed these results. Application of 150–500 nM of the glycolysis inhibitor Chetomin under similar oxygenation conditions led to a sharply reduced expression of both CA IX protein and CA9 mRNA levels, indicating a clear glucose availability involvement for the hypoxic HIF-1α and CA9 expression in GBM cells. Hypoxia significantly influences the behaviour of human tumour cells by activation of genes involved in the adaptation to hypoxic stress. The main objective in malignant GBM therapy is either to eradicate the tumour or to convert it into a controlled, quiescent chronic disease. Aza., SU.D2, Chetomin or CA9-siRNA possesses functional CA9 inhibitory characteristics when applied against human cancers with hypoxic regions like GBM. They may be used as alternative or in conjunction with other direct inhibitors possessing similar functionality, thereby rendering them as potential optimal tools for the development of an optimized therapy in human brain cancer treatment.     

A higher prediagnostic insulin level is a prospective risk factor for incident prostate cancer

A higher insulin level has been linked to the risk of prostate cancer promotion. However, several reports claim that there is no association between a higher insulin level and the risk of incident prostate cancer. In the present report, the insulin hypothesis was tested once more prospectively in men with a benign prostatic disorder. Three hundred and eighty-nine consecutive patients referred with lower urinary tract symptoms without clinical prostate cancer were included during 1994–2002. Follow-up was performed in 2006. Data were obtained from the Swedish National Cancer Register and the Regional Cancer Register, Oncological Centre, Göteborg, Sweden. At this follow-up, 44 of the patients included had developed prostate cancer. Men with prostate cancer diagnosis had a higher systolic (P < 0.001) and diastolic blood pressure (P < 0.000), were more obese as measured by BMI (P = 0.010), waist (P = 0.007) and hip measurements (P = 0.041) than men who did not have prostate cancer diagnosis at follow-up. These men also had a higher uric acid level (P = 0.040), and a higher fasting serum insulin level (P = 0.023) than men who did not have prostate cancer diagnosis at follow-up. Following exclusion of T1a/b prostate cancer cases, the difference of the fasting serum insulin level between the groups was still significant (P = 0.038). Our data support the hypothesis that a higher insulin level is a promoter of prostate cancer. Moreover, our data suggest that the insulin level could be used as a marker of the risk of developing prostate cancer. The present findings also seem to confirm that prostate cancer is a component of the metabolic syndrome. Finally, our data generate the hypothesis that the metabolic syndrome conceals early prostate cancer.     

Évaluation d’une méthode de quantification de la masse métastatique osseuse par mesure automatisée du Bone Scan Index,dans le suivi thérapeutique des cancers du sein

IntroductionThe objective assessment of therapeutic response is a major diagnostic and therapeutic management in breast cancer with bone metastases. The objective of the study was to test performance of an automated method for quantifying the extent of skeletal tumour involvement in breast cancer, using the Bone Scan Index (BSI), and study if BSI could be considered as an imaging biomarker of metastatic bone disease.Materials and methodsOne hundred and two planar bone scans, corresponding to 34 treatment (three successive bone scans) of 31 patients were retrospectively analyzed. Each image was reviewed by two nuclear physicians, a senior and a junior. Exini Bone^® software calculated automatically the BSI for each scan.ResultsAt 3 times of the study, agreements between automatic and visual methods were intermediate: 55.88% (kappa = 0.3704), 52.94% (kappa = 0.3052) and 52.94% (kappa = 0.2173) with junior nuclear physician and 52.94% (kappa = 0.33), 55.88% (kappa = 0.3333) and 50% (kappa = 0.1939) with senior nuclear physician. Six initial bone scans (17%) were considered normal (BSI = 0) by the software; with bone lesions confirmed by morphological imaging and/or histology. Agreements between junior and senior were high, with kappa = 0.81, 0.91 and 0.94 at 3 times of the study. Confrontation with routine analysis showed significant variability with agreements from 47.06 to 76.47%. We did not find any significant relationship between evolution of BSI and tumor markers over time. Only a trend between evolution of CA15-3 and BSI was observed. We did not find any significant association between overall survival and value of BSI.ConclusionIn breast cancer, the fully automated platform of quantifying the BSI seems to have limitations, because of characteristics of bone metastases of breast cancer, and their scintigraphic translation. BSI seems to be an interesting tool, and it could be improved: development of diagnostic “assisted” by computer, combining power of medical knowledge and technical computing could help to score bone disease, and allow standardized monitoring.     

Survival and clinical metastases among prostate cancer patients treated with androgen deprivation therapy in Sweden

ObjectivesTo examine the incidence of metastases and clinical course of prostate cancer patients who are without confirmed metastasis when initiating androgen deprivation therapy (ADT).MethodsRetrospective cohort study conducted using electronic medical records from Swedish outpatient urology clinics linked to national mandatory registries to capture medical and demographic data. Prostate cancer patients initiating ADT between 2000 and 2010 were followed from initiation of ADT to metastasis, death, and/or end of follow-up.ResultsThe 5-year cumulative incidence (CI) of metastasis was 18%. Survival was 60% after 5 years; results were similar for bone metastasis-free survival. The 5-year CI of castration-resistant prostate cancer (CRPC) was 50% and the median survival from CRPC development was 2.7 years. Serum prostate-specific antigen (PSA) levels and PSA doubling time were strong predictors of bone metastasis, any metastasis, and death.ConclusionThis study provides understanding of the clinical course of prostate cancer patients without confirmed metastasis treated with ADT in Sweden. Greater PSA values and shorter PSA doubling time (particularly ≤ 6 months) were associated with increased risk of bone metastasis, any metastasis, and death.     

Sex steroid-induced DNA methylation changes and inflammation response in prostate cancer

BackgroundSex steroid hormones have been reported to induce inflammation causing dysregulation of cytokines in prostate cancer cells. However, the underlying epigenetic mechanism has not well been studied. The objective of this study was to evaluate the effect of sex steroid hormones on epigenetic DNA methylation changes in prostate cancer cells using a signature PCR methylation array panel that correspond to 96 genes with biological function in the human inflammatory and autoimmune signals in prostate cancer. Of the 96-gene panel, 32 genes showed at least 10% differentially methylation level in response to hormonal treatment when compared to untreated cells. Genes that were hypomethylated included CXCL12, CXCL5, CCL25, IL1F8, IL13RAI, STAT5A, CXCR4 and TLR5; and genes that were hypermethylated included ELA2, TOLLIP, LAG3, CD276 and MALT1. Quantitative RT-PCR analysis of select genes represented in a cytokine expression array panel showed inverse association between DNA methylation and gene expression for TOLLIP, CXCL5, CCL18 and IL5 genes and treatment of prostate cancer cells with 5′-aza-2′-deoxycytidine with or without trichostatin A induced up-regulation of TOLLIP expression. Further analysis of relative gene expression of matched prostate cancer tissues when compared to benign tissues from individual patients with prostate cancer showed increased and significant expression for CCL18 (2.6-fold; p < 0.001), a modest yet significant increase in IL5 expression (1.17-fold; p = 0.015), and a modest increase in CXCL5 expression (1.4-fold; p = 0.25). In conclusion, our studies demonstrate that sex steroid hormones can induce aberrant gene expression via differential methylation changes in prostate carcinogenesis.     

Synthesis and biological evaluation of nitric oxide-donating analogues of sulindac for prostate cancer treatment

A series of analogues of the non-steroidal anti-inflammatory drug (NSAID) sulindac 1 were synthesised tethered to nitric oxide (NO) donating functional groups. Sulindac shows antiproliterative effects against immortal PC3 cell lines. It was previously demonstrated that the effect can be enhanced when tethered to NO releasing groups such as nitrate esters, furoxans and sydnonimines. To explore this approach further, a total of fifty-six sulindac–NO analogues were prepared and they were evaluated as NO-releasing cytotoxic agents against prostate cancer (PCa) cell lines. Compounds 1k and 1n exhibited significant cytotoxic with IC₅₀ values of 6.1 ± 4.1 and 12.1 ± 3.2 μM, respectively, coupled with observed nitric oxide release.     

Synthesis and anti-cancer activity of chalcone linked imidazolones

A series of novel chalcone linked imidazolones were prepared and evaluated for their anti-cancer activity against a panel of 53 human tumour cell lines derived from nine different cancer types: leukemia, lung, colon, CNS, melanoma, ovarian, renal, prostate and breast. Some of these hybrids (6, 7 and 8) showed good anti-cancer activity with GI₅₀ values ranging from 1.26 to 13.9 μM. When breast carcinoma cells (MCF-7) were treated with 10 μM concentration of compounds TMAC, CA-4, 6 and 8 cell cycle arrest was observed in G2/M phase. Surprisingly, the increased concentration of the same compound to 30 μM caused accumulation of cells in G0/G1 phase of the cell cycle.     

Family history of non-hematologic cancers among Waldenstrom macroglobulinemia patients: a preliminary study

BackgroundLittle is known about the epidemiology and etiology of Waldenstrom macroglobulinemia (WM). Despite several studies of the relation between family history and B-cell disorders and WM, family history of non-hematologic cancers has not been systematically investigated. We thus examined associations of family history of breast, colorectal, lung, ovarian, and prostate cancers with WM.MethodsAll probands aged 20–79 years with bone marrow biopsy-confirmed diagnosis of WM between May 1, 1999 and January 1, 2010 at the Bing Center for Waldenstrom Macroglobulinemia were eligible for inclusion in our analysis. We reviewed medical records for eligible probands to determine family history of cancer (defined as a cancer diagnosis for ≥1 first-degree relative(s) of the proband). Using expected values constructed from the United States National Health Interview Survey, we estimated age- and race-standardized rate ratios (RRs) for family history of breast, colorectal, lung, ovarian, and prostate cancers by WM subtype.ResultsFamily history of prostate cancer had the largest overall rate ratio (RR = 1.4, 95% confidence limits [CL]: 1.1, 1.7), and among sporadic cases, family history of prostate and breast cancer had the largest rate ratios (prostate: RR = 1.3, 95% CL: 1.1, 1.7; breast: RR = 1.3, 95% CL: 1.2, 1.6).ConclusionOur study suggests that it may be worthwhile to pursue these associations in a case–control study with uniform selection and data collection for cases and controls, and at least some record-based information on family history.     

Biochemical relapse free survival rate in patients with prostate cancer treated with external radiotherapy: outcomes obtained at the CMN Siglo XXI Hospital de Oncología,CMN 20 de Noviembre and Hospital General de México of the México City

AimBiochemical relapse-free survival (bRFS) rate is determined by a cohort of Mexican patients (n = 595) with prostate cancer who received treatment with external radiotherapy.BackgroundPatients with prostate cancer were collected from CMN Siglo XXI (IMSS), CMN 20 de Noviembre (ISSSTE), and Hospital General de México (HGM). For the IMSS, 173 patients that are treated with three-dimensional conformal radiation therapy (3D-CRT) and 250 with SBRT, for the ISSSTE 57 patients are treated with 3D-CRT and on the HGM 115 patients are managed with intensity modulated radiation therapy (IMRT). The percentage of patients by risk group is: low 11.1%, intermediate 35.1% and high 53.8%. The average follow-up is 39 months, and the Phoenix criterion was used to determine the bRFS.Materials and methodsThe Kaplan–Meier technique for the construction of the survival curves and, the Cox proportional hazards to model the cofactors.Results(a) The bRFS rates obtained are 95.9% for the SBRT (7 Gy fx, IMSS), 94.6% for the 3D-CRT (1.8 Gy fx, IMSS), 91.3% to the 3D-CRT (2.65 Gy fx, IMSS), 89.1% for the SBRT (7.25 Gy fx, IMSS), 88.7% for the IMRT (1.8 Gy fx, HGM) %, and 87.7% for the 3D-CRT (1.8 Gy fx, ISSSTE). (b) There is no statistically significant difference in the bRFS rates by fractionation scheme, c) Although the numerical difference in the bRFS rate per risk group is 95.5%, 93.8% and 89.1% for low, intermediate and high risk, respectively, these are not statistically significant.ConclusionsThe RT techniques for the treatment of PCa are statistically equivalent with respect to the bRFS rate. This paper confirms that the bRFS rates of Mexican PCa patients who were treated with conventional vs. hypofractionated schemes do not differ significantly.     

Signification d’une hyperfixation prostatique du fluorodésoxyglucose (18F) chez un patient sans antécédent de cancer de la prostate. Cas cliniques,revue et méta-analyse de la littérature

FDG is not suited for the detection of prostate cancer. However, high prostate uptake demonstrated unexpectedly on FDG PET/CT requested for another indication may lead to the detection of prostate cancer, although a non-malignant origin is more common. We report 4 cases of prostate incidentaloma detected on high FDG prostate uptake, corresponding to 4 typical images and circumstances: diffuse uptake, focal uptake with various levels of SUV_max and of serum PSA level assayed on the basis of PET/CT result. We performed a meta-analysis of the 6 series in the literature currently reporting characterisation of prostate incidentalomas, in a total of 47,935 FDG PET, the average frequency of this incidentaloma is 1.5%; it was characterised in 68% of cases, corresponding to cancer in 16% of characterised cases, adenocarcinoma in 75 cases/78. There was no correlation between the Gleason score and the SUV_max; adenocarcinoma Gleason = 6 can be unexpectedly detected with FDG. Among the risk factors for malignancy, there is a SUV_max > 3, a peripheral location within the prostate and no calcification in the hypermetabolic area. Prostate biopsy may be indicated only in case the management of the patient would be modified if prostate cancer is confirmed; it is prompted in the case of clear elevation of serum PSA level, but also when serum PSA level is normal but there is one or several risk factors on FDG PET/CT images.     

Genistein and daidzein act on a panel of genes implicated in cell cycle and angiogenesis by Polymerase Chain Reaction arrays in human prostate cancer cell lines

Background: The prostate cancer most frequently affects men. The ethnic origin and family antecedents of prostate cancer are established as risk factors. The genetic factors associated with environmental factors such as the nutrition also play a role in the development of the cancer. Epidemiological studies showed that the Asian populations exhibited an incidence of prostate cancer markedly subordinate by comparison with the Western populations. This would be explained partially by their important consumption of soy. Both main phytoestrogens of soy, the genistein and the daidzein, present anti-proliferative properties. Methods: For that purpose, we used different prostate cancer cell lines (LNCaP, DU 145, PC-3) and, by flow cytometry, we determined the concentration of phytoestrogens inducing a cell cycle arrest and the required time of incubation. Results: Then, the effects of 40 μM genistein or 110 μM daidzein for 48 h were determined and studied on the expression of genes involved in the human cell cycle and angiogenesis and conducted by SYBR green quantitative PCR. Conclusion: We demonstrated modulations of cyclin-dependent kinase-related pathway genes, DNA damage-signaling pathway and a down-regulation of EGF and IGF.     

Antiproliferative,antiandrogenic and cytotoxic effects of novel caffeic acid derivatives in LNCaP human androgen-dependent prostate cancer cells

Caffeic acid and its naturally occurring derivative caffeic acid phenethyl ester (CAPE) have antiproliferative and cytotoxic properties in a variety of cancer cell lines without displaying significant toxicity toward healthy cells, and are considered to be potential anticancer agents. However, little is known about their effects on prostate cancer cells. We synthesized and evaluated the effects of caffeic acid, CAPE (2) and 18 synthetic derivatives on cell viability and androgen-dependent cell proliferation, subcellular localisation and expression of androgen receptor (AR) and secretion of prostate-specific antigen (PSA) in LNCaP human hormone-dependent prostate cancer cells. Several synthetic derivatives of CAPE were strong, concentration-dependent cytotoxic agents in LNCaP cells with IC₅₀ values in the 6.8–26.6 μM range, potencies that were up to five-fold greater than that of CAPE (33.7 ± 4.0 μM). A number of caffeic acid derivatives were inhibitors of androgen-stimulated LNCaP cell proliferation with concomitant inhibition of DHT-stimulated PSA secretion. Compound 24 was the most cytotoxic and antiproliferative caffeic acid derivative (IC₅₀ values of 6.8 ± 0.3 and 2.4 ± 0.8 μM, respectively) inhibiting DHT-stimulated cell proliferation and PSA secretion statistically significantly at concentrations as low as 0.3 μM. Exposure to DHT increased cytoplasmic and nuclear AR levels and co-treatment with increasing concentrations of compound 24 or CAPE (2), notably, further increased these levels. In conclusion, a number of synthetic derivatives of caffeic acid are potent inhibitors of androgen-dependent prostate cancer cell proliferation and viability, acting, at least in part, via an antiandrogenic mechanism that involves increased nuclear accumulation of (presumably inactive) AR.