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Natural products remain an important source of drug leads covering unique chemical space and providing significant therapeutic value for the control of cancer and infectious diseases resistant to current drugs. Here, we determined the antiproliferative activity of a natural product manzamine A (1) from an Indo-Pacific sponge following various in vitro cellular assays targeting cervical cancer (C33A, HeLa, SiHa, and CaSki). Our data demonstrated the antiproliferative effects of 1at relatively low and non-cytotoxic concentrations (up to 4 μM). Mechanistic investigations confirmed that 1blocked cell cycle progression in SiHa and CaSki cells at G1/S phase and regulated cell cycle-related genes, including restoration of p21 and p53 expression. In apoptotic assays, HeLa cells showed the highest sensitivity to 1as compared to other cell types (C33A, SiHa, and CaSki). Interestingly, 1decreased the levels of the oncoprotein SIX1, which is associated with oncogenesis in cervical cancer. To further investigate the structure–activity relationship among manzamine A (1) class with potential antiproliferative activity, molecular networking facilitated the efficient identification, dereplication, and assignment of structures from the manzamine class and revealed the significant potential in the design of optimized molecules for the treatment of cervical cancer. These data suggest that this sponge-derived natural product class warrants further attention regarding the design and development of novel manzamine analogues, which may be efficacious for preventive and therapeutic treatment of cancer. Additionally, this study reveals the significance of protecting fragile marine ecosystems from climate change-induced loss of species diversity.

Prostate cancer is a significant health problem for men in the United States. While useful treatment modalities are available, their therapeutic efficacies are limited and severe side effects remain a concern. Alternatively, immunotherapy represents one of the most valuable treatments by inducing immune response targeting tumor cells. Sipuleucel-T is the only FDA approved immunotherapeutic agent for the treatment of patients with metastatic castration-resistant prostate cancer. Overall survival benefit with sipuleucel-T is modest, and the research field of cancer immunotherapy is continuously expanding. Numerous methods designed to induce tumor-specific immunity are at various developmental stages in clinical and preclinical studies. Among such modalities, the use of adenovirus vector (Ad) as an immunotherapy agent to deliver tumor-associated antigens is an attractive and versatile vector system. In this review, we describe the potential use of Ad-vector for prostate cancer immunotherapy.

In United States, prostate cancer is the most common cancer diagnosis (excluding dermatological malignancies) and the second leading cause of cancer related mortality in men [1]. Early stage prostate cancer has an indolent course; however local tumor progression and aggressive metastatic disease may develop in the long term [2]. Androgen deprivation therapy provides disease control for a substantial period of time; however the vast majority eventually progress [3, 4]. In hormone refractory cases, chemotherapy with docetaxel and prednisone led to a superior survival and quality of life [5]. This combination remained as the predominant first line of chemotherapeutic option for a significant period of time. Only recently have new advances in chemotherapeutic, anti-androgen and other novel therapeutic options made it into the clinic. Sipuleucel-T in patients with castration-resistant metastatic prostate cancer demonstrated a reduction in the risk of death [6]. The sipuleucel-T trial results have helped demonstrate a proof of concept of the potential of immunotherapy in prostate cancer but widespread acceptance of its use has been tempered by the time limited survival advantage of only four months. Therefore, we continue to need novel agents and combination strategies which build on this initial success. Several other inter-related patho-physiological mechanisms like inflammation and genetic/epigenetic modulation are under investigation in prostate cancer which could have further implications in the development of these new immunotherapeutic preventive and treatment strategies [7, 8]. In this article we will give an overview about the role and link of inflammation, epigenetic modulation and immune modulation in the development and treatment of prostate cancer. It is imperative that new approaches that further define immune responsiveness and identify which patients are most likely to benefit. With the increasing availability of novel agents, future advances will also lie in innovative combination strategies.

An increased understanding of basic immunology, combined with the identification of various tumour-associated antigens, has fuelled the development of novel immunotherapy approaches for various cancers, including prostate cancer. In this Review, Karan and colleagues describe various active immunotherapy approaches that have the potential to transform the way in which patients with prostate cancer are treated. They also highlight future areas of research that might help to improve the efficacy of immunotherapy for prostate cancer.

Neuroendocrine (NE) cells are the minor cell populations in normal prostate epithelial compartments. During prostate carcinogenesis, the number of NE cells in malignant lesions increases, correlating with its tumorigenicity and hormone-refractory growth. It is thus proposed that cancerous NE cells promote prostate cancer (PCa) cell progression and its androgen-independent proliferation, although the origin of the cancerous NE cells is not clear. To investigate the role of cancerous NE cells in prostate carcinogenesis, we characterized three NE subclone cell lines–NE-1.3, NE-1.8 and NE-1.9, which were transdifferentiated from androgen-sensitive human PCa LNCaP cells by culturing in an androgen-depleted environment, resembling clinical androgen-ablation therapy. These subclone cells acquire many features of NE cells seen in clinical prostate carcinomas, for example exhibiting a neuronal morphology and expressing multiple NE markers, including neuron-specific enolase, chromogranin B, neurotensin, parathyroid hormone-related peptide, and to a lesser degree for chromogranin A, while lacking androgen receptor (AR) or prostate specific antigen (PSA) expression. These cells represent terminally differentiated stable cells because after 3 months of re-culturing in a medium containing androgenic activity, they still retained the NE phenotype and expressed NE markers. Despite these NE cells having a slow growth rate, they readily developed xenograft tumors. Furthermore, media conditioned by these NE cells exhibited a stimulatory effect on proliferation and PSA secretion by LNCaP cells in androgen-deprived conditions. Additionally, we found that receptor protein tyrosine phosphatase α plays a role in upregulating multiple NE markers and acquiring the NE phenotype. These NE cells thus represent cancerous NE cells and could serve as a useful cell model system for investigating the role of cancerous NE cells in hormone-refractory proliferation of PCa cells.

Neuroendocrine (NE) cells are the minor cell populations in normal prostate epithelial compartments. During prostate carcinogenesis, the number of NE cells in malignant lesions increases, correlating with its tumorigenicity and hormone-refractory growth. It is thus proposed that cancerous NE cells promote prostate cancer (PCa) cell progression and its androgen-independent proliferation, although the origin of the cancerous NE cells is not clear. To investigate the role of cancerous NE cells in prostate carcinogenesis, we characterized three NE subclone cell lines–NE-1.3, NE-1.8 and NE-1.9, which were transdifferentiated from androgen-sensitive human PCa LNCaP cells by culturing in an androgen-depleted environment, resembling clinical androgen-ablation therapy. These subclone cells acquire many features of NE cells seen in clinical prostate carcinomas, for example exhibiting a neuronal morphology and expressing multiple NE markers, including neuron-specific enolase, chromogranin B, neurotensin, parathyroid hormone-related peptide, and to a lesser degree for chromogranin A, while lacking androgen receptor (AR) or prostate specific antigen (PSA) expression. These cells represent terminally differentiated stable cells because after 3 months of re-culturing in a medium containing androgenic activity, they still retained the NE phenotype and expressed NE markers. Despite these NE cells having a slow growth rate, they readily developed xenograft tumors. Furthermore, media conditioned by these NE cells exhibited a stimulatory effect on proliferation and PSA secretion by LNCaP cells in androgen-deprived conditions. Additionally, we found that receptor protein tyrosine phosphatase α plays a role in upregulating multiple NE markers and acquiring the NE phenotype. These NE cells thus represent cancerous NE cells and could serve as a useful cell model system for investigating the role of cancerous NE cells in hormone-refractory proliferation of PCa cells.

Molecular genetic mechanisms involved in the progression of prostate cancer are not well understood due to extensive tumor heterogeneity and lack of suitable models. New methods such as fluorescence in-situ hybridization (FISH), comparative genomic hybridization (CGH) and microsatellite analysis have documented losses or gains on various chromosomes. Altered chromosomal regions have been associated with the activation of oncogenes and the inactivation of tumor suppressor genes or defects in mismatch repair (MMR) genes. It is suggested that increased genomic instability is associated with decreased androgen-responsive and progressive behavior of human prostate tumors, but it remains unclear whether this genomic instability is causing the progression of cancer or is the consequence of cancer. Extended studies on hereditary prostate cancer have identified 7 prostate cancer susceptibility loci on several chromosomes, but no specific gene has been confined for a large proportion of susceptibility. In this review we summarize the ongoing molecular genetic events associated with the sporadic and hereditary prostate cancer development and progression. © 2002 Wiley-Liss, Inc.

Because of the heterogeneous nature of prostate cancer, identifying the molecular mechanisms involved during the transition from an androgen-sensitive to an androgen-independent phenotype is very complex. An LNCaP cell model that recapitulates prostate cancer progression, comprising early passage androgen-sensitive (LNCaP-C33) and late passage androgen-independent (LNCaP-C81) phenotypes, would help to provide a better understanding of such molecular events. In this study, we examined the genes expressed by LNCaP-C33 and LNCaP-C81 cells using cDNA microarrays containing 1176 known genes. This analysis demonstrated that 34 genes are up-regulated and eight genes are down-regulated in androgen-independent cells. Northern blot analysis confirmed the differences identified by microarrays on several candidate genes, including c-MYC, c-MYC purine-binding transcription factor (PuF), macrophage migration inhibitory factor (MIF), macrophage inhibitory cytokine-1 (MIC-1), lactate dehydrogenase-A (LDH-A), guanine nucleotide-binding protein Gi, α-1 subunit (NBP), cyclin dependent kinase-2 (CDK-2), prostate-specific membrane antigen (PSM), cyclin H (CCNH), 60S ribosomal protein L10 (RPL10), 60S ribosomal protein L32 (RPL32), and 40S ribosomal protein S16 (RPS16). These differentially-regulated genes are correlated with progression of human prostate cancer and may be of therapeutic relevance as well as an aid in understanding the molecular genetic events involved in the development of this disease's hormone-refractory behavior.

Because of the heterogeneous nature of prostate cancer, identifying the molecular mechanisms involved during the transition from an androgen-sensitive to an androgen-independent phenotype is very complex. An LNCaP cell model that recapitulates prostate cancer progression, comprising early passage androgen-sensitive (LNCaP-C33) and late passage androgen-independent (LNCaP-C81) phenotypes, would help to provide a better understanding of such molecular events. In this study, we examined the genes expressed by LNCaP-C33 and LNCaP-C81 cells using cDNA microarrays containing 1176 known genes. This analysis demonstrated that 34 genes are up-regulated and eight genes are down-regulated in androgen-independent cells. Northern blot analysis confirmed the differences identified by microarrays on several candidate genes, including c-MYC, c-MYC purine-binding transcription factor (PuF), macrophage migration inhibitory factor (MIF), macrophage inhibitory cytokine-1 (MIC-1), lactate dehydrogenase-A (LDH-A), guanine nucleotide-binding protein Gi, alpha-1 subunit (NBP), cyclin dependent kinase-2 (CDK-2), prostate-specific membrane antigen (PSM), cyclin H (CCNH), 60S ribosomal protein L10 (RPL10), 60S ribosomal protein L32 (RPL32), and 40S ribosomal protein S16 (RPS16). These differentially-regulated genes are correlated with progression of human prostate cancer and may be of therapeutic relevance as well as an aid in understanding the molecular genetic events involved in the development of this disease's hormone-refractory behavior.

Acetyl-CoA-Synthetase (ACS) is involved in the production of acetate, a major metabolite in numerous organisms. There are two forms of this enzyme: ADP-forming ACSand ATP-forming ACS. We focus mainly on the AMP-forming ACSgene, which is relatively well conserved in eubacteria, archeaebacteria, and eukaryotes. BLAST searches in databases showed 30 protein sequences significantly related to the ACS. Most of these sequences were identified as ACSbut three of them, belonging to the mammalian species, were annotated as another gene named: the SAgene, which is involved in the essential hypertension. The ACSand SAgenes probably derived from a duplication of an ancestral gene but have acquired different functions. Six conserved regions of the ACSprotein were defined across the three domains of life. While the precise function of the conserved regions remains unknown, they are probably involved in the enzymatic activity. Among eukaryotes, we found a high variability with respect to the number and the position of introns. However, some positions are conserved between fungi and a nematode. A maximum likelihood tree based upon the conserved regions showed that all sequences except the one from B.subtilis, belong to two basic groups: one the SA-like group including sequences from Archaeoglobusfulgidusand Streptomycescoelicolor, and second, the ACSgroup. The later can be further divided in two parts: a prokaryotic one including eubacteria and an archaebacterium, and a eukaryotic group within which two proteobacterial sequences branch including ACSfrom the α-proteobacterium Rhodobactercapsulatus. Within the eukaryotic group, bootstrap support is very low, but overall the data are consistent with the view that eukaryotes acquired their ACSgene from the ancestors of mitochondria. The localization of this enzyme in eukaryotic mitochondria is the additional evidence in favor of this interpretation.

We analyzed natural populations of Zaprionus indianusin 10 Indian localities along a south-north transect (latitude: 10–31°3 N). Size traits (body weight, wing length and thorax length) as well as a reproductive trait (ovariole number) followed a pattern of clinal variation, that is, trait value increased with latitude. Wing/thorax ratio, which is inversely related to wing loading, also had a positive, but non-significant correlation with latitude. By contrast, bristle numbers (sternopleural and abdominal) exhibited a non-significant but negative correlation with latitude. Sex dimorphism, estimated as the female/male ratio, was very low in Z. indianus, contrasting with results already published in other species. Genetic variations among populations were also analyzed according to other geographic parameters (altitude and longitude) and to climatic conditions from each locality. A significant effect of altitude was found for size traits. For abdominal bristles, a multiple regression technique evidenced a significant effect of both latitude and altitude, but in opposite directions. Genetic variations were also correlated to climate, and mainly with average year temperature. Taking seasonal variations into account failed however to improve the predictability of morphometrical variations. The geographic differentiation of Z.indianusfor quantitative traits suggests adaptive response to local conditions, especially to temperature, but also reveals a complex situation according to traits investigated and to environmental parameters, which does not match results on other drosophilid species.

Indian geographical populations ofDrosophila melanogaster, collected at latitude 10–32.3 °N, longitude 76.1–80.1 °E and altitude 16–2050 m, were analysed for changes inAdhFfrequency and utilization potential of diverse alcoholic resources. Until now, there have been limited data on climatic association of correlated changes on these aspects in continental populations ofD. melanogaster. Indian populations demonstrate an increase inAdhFfrequency by 0.04 per degree latitude and significantly higher utilization of ethanol (9.0–15.2%), acetic acid (8.1–12.5%), n-propanol (2.55–4.25%), 2-propanol (1.5–3.5%), n-butanol (2.15–3.5%) and 2-butanol (0.68–1.2%). Data also revealed significant correlation with latitude as well as altitude. Regression analysis of climatic data from collection sites confirmed the observed clinal variation ofAdhFas well as alcoholic utilization inD. melanogaster. On the Indian subcontinent, variation inAdhFfrequency and alcoholic resource utilization along increasing latitude as well as altitude are due to climatic selection factors such as temperature and rainfall.

Abstract: In five Indian localities, it was possible to collect D. melanogaster in two different types of habitats, namely ordinary domestic and alcohol rich ones. Tolerance and utilization capacity of several alcohols and of acetic acid were analyzed in a total of 10 local populations. Results on two other species (D. repleta and D. immigrans) were also available from one place. In each locality, the population from alcohol rich habitat proved to be more tolerant to all the investigated products and also to be more capable of using them as a resource. Alcohols toxicity increased with increasing carbon chain length and secondary alcohols were more toxic than primary ones. Utilization capacity of all products was relatively independent of their toxicity. Especially acetic acid, the toxicity of which was low and similar to that of ethanol, was always a fairly poor resource. From a genetic point of view, tolerance and utilization capacity appeared as two relatively independent traits. Natural selection, which is responsible for the genetic differentiation of local populations, is likely to act simultaneously on both traits.

Indian geographical populations of Drosophila melanogaster,collected at latitude 10–32.3 oN, longitude 76.1–80.1 oE and altitude 16–2050 m, were analysed for changes in Adh1frequency and utilization potential of diverse alcoholic resources. Until now, there have been limited data on climatic association of correlated changes on these aspects in continental populations of D. melanogaster.Indian populations demonstrate an increase in AdhFfrequency by 0.04 per degree latitude and significantly higher utilization of ethanol (9.0–15.2%), acetic acid (8.1–12.5%), n‐propanol (2.55‐4.25%), 2‐propanol (1.5‐3.5%), n‐butanol (2.15 3.5%) and 2‐butanol (0.68‐1.2%). Data also revealed significant correlation with latitude as well as altitude. Regression analysis of climatic data from collection sites confirmed the observed clinal variation of AdhFas well as alcoholic utilization in D. melanogaster.On the Indian subcontinent, variation in AdhFfrequency and alcoholic resource utilization along increasing latitude as well as altitude are due to climatic selection factors such as temperature and rainfall.

There are significant geographical variations for four quantitative traits among eight natural populations of Drosophzla kikkawai along the Indian latitudinal transect (8.29 to 33°N). Body weight, wing length, thorax length, and ovariole number exhibit significant clinal variation with increase in latitutde. Genetic correlations between all the four traits are significantly higher. Slope values for body weight and wing length are higher (2.32 per degree latitude) while lower for thorax length (0.70) and ovariole number (0.56). South Indian populations are characterised by lower mean values but higher variances as well as CV values as compared with northern populations. Multiple regression analyses (on the basis of temperature related climatic variables) evidence significantly higher association between all the four traits and coefficient of variation of mean annual temperature (seasonal thermal amplitude; TCV). Thus, genetic differentiations for quantitative traits in D. kikkaivai are due to selective pressure from variable seasonal environmental conditions occurring on the southern tropical versus northern subtropical regions of the Indian subcontinent.

Natural populations of Drosophila kikkawai were collected in India and Sri Lanka, along a latitudinal transect ranging from 6·8° to 31·8° N latitude. Six morphometrical traits were analysed: wing and thorax length, body weight, ovariole number, and abdominal and sternopleural bristle numbers. Significant clines were observed for the three size-related traits and for ovariole number, corresponding to a regular increase in the mean value with latitude, but not for bristle numbers. Due to the utilization of two types of laboratory food, data were distributed into two separate data sets. A low-nutrient food produced smaller flies on average because of more intense crowding. The two rearing conditions produced significant clines but with significantly different slopes. The wing/thorax ratio, which is inversely related to wing loading, also increased with latitude. The analysis of Indian climatic conditions suggested that winter temperature, decreasing from south to north, could be more efficient than summer temperature, which varies in an opposite way, as a selective factor for inducing the clinal variations. The sibling species D. leontia, which is known only from the humid tropics, was found to be much smaller than D. kikkawai and did not fit the clinal regressions. Such morphological differences should help to identify the two species when found in sympatry.