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In this study we have identified POLθ-S6K-p62 as a novel druggable regulator of radiation response in prostate cancer. Despite significant advances in delivery, radiotherapy continues to negatively affect treatment outcomes and quality of life due to resistance and late toxic effects to the surrounding normal tissues such as bladder and rectum. It is essential to develop new and effective strategies to achieve better control of tumor. We found that ribosomal protein S6K (RPS6KB1) is elevated in human prostate tumors, and contributes to resistance to radiation. As a downstream effector of mTOR signaling, S6K is known to be involved in growth regulation. However, the impact of S6K signaling on radiation response has not been fully explored. Here we show that loss of S6K led to formation of smaller tumors with less metastatic ability in mice. Mechanistically we found that S6K depletion reduced NFκB and SQSTM1 (p62) reporter activity and DNA polymerase θ (POLθ) that is involved in alternate end-joining repair. We further show that the natural compound berberine interacts with S6K in a in a hitherto unreported novel mode and that pharmacological inhibition of S6K with berberine reduces Polθ and downregulates p62 transcriptional activity via NFκB. Loss of S6K or pre-treatment with berberine improved response to radiation in prostate cancer cells and prevented radiation-mediated resurgence of PSA in animals implanted with prostate cancer cells. Notably, silencing POLQ in S6K overexpressing cells enhanced response to radiation suggesting S6K sensitizes prostate cancer cells to radiation via POLQ. Additionally, inhibition of autophagy with CQ potentiated growth inhibition induced by berberine plus radiation. These observations suggest that pharmacological inhibition of S6K with berberine not only downregulates NFκB/p62 signaling to disrupt autophagic flux but also decreases Polθ. Therefore, combination treatment with radiation and berberine inhibits autophagy and alternate end-joining DNA repair, two processes associated with radioresistance leading to increased radiation sensitivity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

In the field of molecular self-assembly, the core of an assembly is always made up of hydrophobic moiety like a long alkyl chain, whereas the outer part has always been a hydrophilic moiety such as poly(ethylene glycol) (PEG), or charged species. Hence, reversing the trend to manifest self-assembled structures with a PEG core and a surface consisting of alkyl chains in aqueous system is incredibly challenging. Herein, we architected a unique class of cationic bolaamphiphiles containing low molecular weight PEG and alkyl chains of different lengths. The bolaamphiphiles spontaneously form vesicles without external stimuli. These vesicles are unprecedented because PEG makes up the vesicle core, while the alkyl chains appear on the vesicles' exterior. Hence, this particular design reverses the usual trend of self-assembly formation. The vesicle size increases with the increase in alkyl chain-length. To our great surprise, we obtained large micelles for longest alkyl-chain amphiphile, which in turn act as a gemini amphiphile. The shift from a particular bolaamphiphile to gemini amphiphile with the variation of alkyl chain is also unexplored. Therefore, this specific class of self-assembled structure would compound a new paradigm in molecular self-assembly and supramolecular chemistry., (© 2024 Wiley-VCH GmbH.)

The continued emergence and spread of drug-resistant pathogens and the decline in the approval of new antimicrobial drugs pose a major threat to managing infectious diseases, resulting in high morbidity and mortality. Even though a significant variety of antibiotics can effectively cure many bacterial infectious diseases, microbial infections remain one of the biggest global health problems, which may be due to the traditional drug delivery system's shortcomings which lead to poor therapeutic index, low drug absorption, and numerous other drawbacks. Further, the use of traditional antibiotics to treat infectious diseases has always been accompanied by the emergence of multidrug resistance and adverse side effects. Despite developing numerous new antibiotics, nanomaterials, and various techniques to combat infectious diseases, they have persisted as major global health issues. Improving the current antibiotic delivery systems is a promising approach to solving many life-threatening infections. In this context, nanoliposomal systems have recently attracted much attention. Herein, we attempt to provide a concise summary of recent studies that have used liposomal nanoparticles as delivery systems for antibacterial medicines. The minireview also highlights the enormous potential of liposomal nanoparticles as antibiotic delivery systems. The future of these promising approaches lies in developing more efficient delivery systems by precisely targeting bacterial cells with antibiotics with minimum cytotoxicity and high bacterial combating efficacy., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Exposure to sunlight, mainly UVA, leads to typical changes in the features of the skin known as photoaging. UVA irradiation induces the expression of proteases that are responsible for the degradation of the extracellular matrix proteins to results in photoaging; it also downregulates the expression of proteins that are needed for the skin structure. Since, it is known that cells in the neighborhood of irradiated cells, but not directly exposed to it, often manifest responses like their irradiated counterparts, it is important to evaluate if these bystander cells too, can contribute to photoaging. UVA induced cell cycle arrest has been associated with photoaging, from flow cytometry analysis we found that there was an induction of cell cycle arrest at the G 1 /S phase in the UVA-bystander cells. The expression of some key photoaging marker genes likes, matrix metalloproteinases (MMP-1, MMP-3, MMP-9), cyclooxygenase-2 (COX-2), collagen1 and elastin were assessed from qRT-PCR. Up-regulation of MMP-1 and COX-2, downregulation of collagen1 and elastin, along with suppression below normal expression for MMP-3 and MMP-9 was observed in the UVA-bystander A375 cells. Our findings suggest that UVA-bystander cells may contribute to the process of photoaging., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Emerging evidence suggests an important role for SIRT1, a nicotinamide adenine dinucleotide (NAD)-dependent deacetylase in cancer development, progression and therapeutic resistance; making it a viable therapeutic target. Here, we examined the impact of resveratrol-mediated pharmacological activation of SIRT1 on the progression of HGPIN lesions (using the Pten -/- mouse model) and on prostate tumor development (using an orthotopic model of prostate cancer cells stably silenced for SIRT1). We show that precise SIRT1 modulation could benefit both cancer prevention and treatment. Positive effect of SIRT1 activation can prevent Pten deletion-driven development of HGPIN lesions in mice if resveratrol is administered early (pre-cancer stage) with little to no benefit after the establishment of HGPIN lesions or tumor cell implantation. Mechanistically, our results show that under androgen deprivation conditions, SIRT1 inhibition induces senescence as evidenced by decreased gene signature associated with negative regulators of senescence and increased senescence-associated β-galactosidase activity. Furthermore, pharmacological inhibition of SIRT1 potentiated growth inhibitory effects of clinical androgen receptor blockade agents and radiation. Taken together, our findings provide an explanation for the discrepancy regarding the role of SIRT1 in prostate tumorigenesis. Our results reveal that the bifurcated roles for SIRT1 may occur in stage and context-dependent fashion by functioning in an antitumor role in prevention of early-stage prostate lesion development while promoting tumor development and disease progression post-lesion development. Clinically, these data highlight the importance of precise SIRT1 modulation to provide benefits for cancer prevention and treatment including sensitization to conventional therapeutic approaches., (© 2022 Wiley Periodicals LLC.)

Zinc oxide (ZnO) nanostructures can be synthesized in nanoforms of spheres, rods, flowers, disks, walls, etc., among which nanoflowers have gained special attention due to their versatile biomedical and pollutant remedial applications in waste water and air. ZnO nanoflowers have an ultrasmall size with a huge surface area to volume ratio due to their hexagonal petal structures which render them superior compared to the nanoparticles of other shapes. The ZnO nanoflowers have bandgap energy equivalent to a semiconductor that makes them have unique photophysical properties. We have used the appropriate keywords in Google Scholar and PubMed to obtain the recent publications related to our topic. We have selected the relevant papers and utilized them to write this review. The different methods of synthesis of ZnO nanoflowers are chemical vapor deposition, facile hydrothermal, thermal evaporation, chemical reduction, bio route of synthesis, and solvothermal method, etc. which are mentioned in this review. ZnO nanoparticles are used in paints, cosmetics, and other products due to their high photocatalytic activity. The different applications of ZnO nanoflowers in the diagnosis of disease biomarkers, biosensors, catalysts, and the therapeutic process along with wastewater remediation and gas sensing applications will be discussed in this review., Competing Interests: The authors declare no conflict of interest., (© 2022 The Author(s).)

Background: Cisplatin has been extensively used in therapeutics for its broad-spectrum anticancer activity and frequently used for the treatment of solid tumors. However, it presents several side-effects and several cancers develop resistance. Combination therapy of cisplatin with poly (ADP-ribose) polymerase 1 (PARP1) inhibitors has been effective in increasing its efficacy at lower doses., Methods and Results: In this work, we have shown that the nitro-flavone derivative, 2-(4-Nitrophenyl)-4H-chromen-4-one (4NCO), can improve the sensitivity of cancer cells to cisplatin through inhibition of PARP1. The effect of 4NCO on cisplatin toxicity was studied through combination therapy in both exponential and density inhibited A375 melanoma cells. Combination index (CI) was determined from isobologram analysis. The mechanism of cell killing was assessed by lactate dehydrogenase (LDH) assay. Temporal nicotinamide adenine dinucleotide (NAD + ) assay was done to show the inhibition of PARP1. We also performed in silico molecular modeling studies to know the binding mode of 4NCO to a modeled PARP1-DNA complex containing cisplatin-crosslinked adduct. The results from both in silico and in cellulo studies confirmed that PARP1 inhibition by 4NCO was most effective in sensitizing A375 melanoma cells to cisplatin. Isobologram analysis revealed that 4NCO reduced cell viability both in exponential and density inhibited A375 cells synergistically. The combination led to cell death through apoptosis., Conclusion: The synthetic nitro-flavone derivative 4NCO effectively inhibited the important nuclear DNA repair enzyme PARP1 and therefore, could complement the DNA-damaging anticancer drug cisplatin in A375 cells and thus, could act as a potential adjuvant to cisplatin in melanoma therapy., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

Acridines are an important class of bioactive molecules having varied uses. Its derivative, 9-phenylacridine (ACPH) had been found to exhibit antitumor activity both in cell lines and in vivo model. Its DNA binding ability and absorbance in the ultraviolet range encouraged us to investigate its role as a photosensitizer with UVA radiation. We investigated the effects of ACPH prior to UVA exposure on in vitro DNA through photo-cleavage assay. Effect of such treatment was also studied in cultured A375 melanoma cells. Endpoints studied included morphological changes, evaluation of cellular viability, scratch assay, intracellular reactive oxygen species (ROS) production, DNA damage, lipid peroxidation, glutathione (GSH) level, autophagy, cell cycle progression, depletion of mitochondrial membrane potential (ΔΨmt), induction of apoptosis and Hoechst dye efflux assay. Our findings indicated that ACPH could sensitize damage to DNA induced by UVA both in vitro and in cells. It could also potentiate cell killing by UVA. It arrested cells in G 2 /M phase and induced apoptotic death through mitochondria mediated pathway. This sensitization was through enhancement of intracellular ROS. Our findings also indicated that the stem cells side population was reduced on such treatment. The findings are important as it indicates ACPH as a promising photosensitizer and indicates its possible role in photodynamic therapy., (© 2020 The Author(s).)

The development of efficient, biodegradable and biocompatible surfactants has become a pressing need because of adverse effects of surface-active compounds on the aquatic environment and human health. Cleavable surfactants containing a labile functional group have the ability to eliminate some of these problems. Consequently, PEGylated amphiphiles have found widespread applications in pharmaceutics, household purposes, and drug delivery. Herein we report synthesis and characterization of two novel amphiphiles which to our knowledge are the first examples of double PEG-tailed amphiphiles with an anionic head group. Considering their chemical structure, they are expected to be biodegradable, biocompatible, milder and less irritant than conventional surfactants. The solution behavior of these newly developed amphiphiles was thoroughly investigated in aqueous buffer (pH 7.0) at 25 °C. The surface activity of the compounds in aqueous buffer was studied by surface tension measurements. The self-assembly properties were investigated by various techniques such as fluorescence and NMR spectroscopy, dynamic light scattering, transmission electron microscopy, atomic force microscopy, and isothermal titration calorimetry. Both molecules were found to be surface active in water and exhibit spontaneous vesicle formation in the absence of any additives at room temperature. As in the cases of conventional surfactants, the self-assembly is driven by the hydrophobic effect. The vesicles produced in aqueous media were shown to encapsulate hydrophobic dyes and exhibit structural transitions upon addition of salts. The sensitivity of the vesicles to change in environments qualifies them for potential use in drug delivery., Competing Interests: The authors declare no competing financial interests., (This journal is © The Royal Society of Chemistry.)

The bottom-up approach of supramolecular polymerization is an effective synthetic method for functional organic nanostructures. However, the uncontrolled growth and polydisperse structural outcome often lead to low functional efficiency. Thus, precise control over the structural characteristics of supramolecular polymers is the current scientific hurdle. Research so far has tended to focus on systems with inherent kinetic control by the presence of metastable state monomers either through conformational molecular design or by exploring pathway complexity. The need of the hour is to create generic strategies for dormant states of monomers that can be extended to different molecules and various structural organizations and dimensions. Here we venture to demonstrate chemical reaction-driven cooperative supramolecular polymerization as an alternative strategy for the controlled synthesis of organic two-dimensional nanostructures. In our approach, the dynamic imine bond is exploited to convert a non-assembling dormant monomer to an activated amphiphilic structure in a kinetically controlled manner. The chemical reaction governed retarded nucleation-elongation growth provides control over dispersity and size., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

PEGylated vesicles are known to serve as blood-persistent drug-delivery systems (DDSs) with potential applications in intravenous drug administration. pH-responsive PEGylated vesicles are also among the most promising stimuli-responsive carriers for drug delivery and controlled release for cancer chemotherapy. Herein, we report design and synthesis of two novel pH-responsive amphiphiles by coupling a cholesterol (Chol) and poly(ethylene glycol) chain with l-cysteine amino acid through hydrolysable linkages. The objective of this work is to physicochemically characterize the nanoaggregates of the amphiphiles under different experimental conditions. We have demonstrated spontaneous vesicle formation by the amphiphiles in water using various spectroscopic, calorimetric, and microscopic techniques. The size of vesicles was observed to increase on reduction of solution pH and increase in amphiphile concentration. The vesicles were found to be sufficiently stable under physiological conditions and were shown to be able to encapsulate not only hydrophilic dyes in their aqueous core but also hydrophobic guest molecules in the bilayer membrane constituted by the Chol units. These nanosized vesicles exhibit pH-triggered release of encapsulated dye molecules in acidic pH. Thus, these spontaneously formed stable vesicles might hold potential as biocompatible DDSs in cancer chemotherapy.

Antitumor potential of a 1,4-dihydropyridine derivative (DHP-8) has been successfully studied previously in a number of cancer cell lines including the human melanoma cells, A375. In order to validate its anticancer activity, DMBA induced tumor in Swiss Albino mice was considered for this study. DMBA causes skin carcinoma in murine systems and is an important in vivo model for evaluating the efficacy of any new chemical entity against skin cancer. Topical administration of DHP-8 at the dose rate of 33.3 and 50.0 mg/kg body weight showed a significant reduction in tumor parameters. It also prevented the progression and differentiation of squamous cell carcinoma, as evidenced from histopathological studies. Immunohistochemical analysis for the expression of Ki67 indicated that it also reduced cancer cell proliferation. Additionally, it induced apoptosis in the tumor cells by activation of Caspase3. Our results indicated that DHP-8 efficiently attenuated DMBA induced tumor progression and it could be a potent therapeutic agent for skin cancer treatment.

The general transcription factor E2F1 reportedly functions in a protumorigenic manner in several cancer models. We show that the genetic context of cancer cells influence E2F1's role to impede the protumorigenic role. Thirty to fifty percent of melanoma patients carry mutant BRAF with about 90% of mutant BRAF melanomas being V 600E mutation. Tissue microarrays from melanoma patients were used to establish an association between E2F1 and BRAF V600E . We show for the first time that low E2F1 levels in BRAF V600E melanomas are associated with lymph node metastasis. Genetic manipulation of E2F1 in BRAF V600E and BRAF wt cells were used to determine its role in malignant melanoma progression by examining effects on migration and invasion. E2F1-mediated negative regulation of myosin light chain kinase (MYLK) increased migration and invasion in BRAF V600E cells by phosphorylating myosin light chain and increased stress fiber formation. We show that E2F1 inhibits extracellular signal-regulated kinase (ERK) activation in BRAF V600E cells and provide evidence for a negative feedback loop between E2F1 and ERK in these cells. This study shows for the first time that E2F1 has a cancer protective role in oncogenic BRAF-activated melanoma cells and that loss of E2F1 can allow disease progression through a novel mechanism of E2F1-mediated MYLK regulation. This study has implications for oncogenic BRAF-activated tumors and resistance to targeted oncogenic BRAF therapy., (© 2019 Wiley Periodicals, Inc.)

Published evidence shows a correlation between several molecular markers and prostate cancer (PCa) progression including in African Americans (AAs) who are disproportionately affected. Our early detection efforts led to the identification of elevated levels of antiapoptotic protein, c-FLIP and its upstream regulatory factors such as androgen receptor (AR), recepteur d'origine nantais (RON), a receptor tyrosine kinase in human prostate tumors. The primary objective of this study was to explore whether these markers play a role in racial disparities using immunohistochemistry in prostatectomy samples from a cohort of AA, Hispanic Whites (HWs), and non-Hispanic Whites (NHWs). Bivariable and multivariable logistic regression analyses were used to identify a statistical association between molecular markers, possible correlation with risk factors including race, obesity, prostate-specific antigen (PSA) and disease aggressiveness. Further, changes in the levels and expression of these molecular markers were also evaluated using human PCa cell lines. We found significantly elevated levels of RON ( P = 0.0082), AR ( P = 0.0001), c-FLIP ( P = 0.0071) in AAs compared with HWs or NHWs. Furthermore, a higher proportion of HW and NHWs had a high Gleason score (>6) but not PSA as compared to AAs ( P = 0.032). In summary, our findings suggest that PSA was important in predicting aggressive disease for the cohort overall; however, high levels of RON may play a role in predisposing AA men to develop aggressive disease. Future research is needed using large datasets to confirm these findings and to explore whether all or any of these markers could aid in race-specific stratification of patients for treatment., (© 2019 Wiley Periodicals, Inc.)

1,4-Dihydropyridines (1,4-DHPs) are important as a class of heterocyclic compounds that exhibit wide range of biological actions. Many of its derivatives are already characterized as medicinally important drugs and used worldwide. In this study, we have screened some novel Hantzsch 1,4-DHP compounds using both in silico (QSAR and Pharmacophore) and in vitro (cytotoxic screening). 1,4-DHP showed selective cytotoxicity against five human cancerous cell lines; A375, A549, HeLa, HepG2 and SH-SY5Y but limited effect towards normal skin keratinocyte (HaCaT), lung fibroblast (WL-38) and healthy peripheral blood mononuclear cells. In A375 and HepG2 cells, one of the 1,4-DHP derivative (DHP-8) was found to inhibit cell proliferation, and simultaneously increased the apoptotic population as well as mitochondrial membrane depolarization. Furthermore, the mitochondrial signal was triggered with the activation of cleaved Caspase9, Caspase3 and PARP. The treatment with DHP-8 also increased the expression level of SIRT1, subsequently decreasing the level of pAKT ser473 and survivin. Reduced pAKT ser473 expression led to decrease the phosphorylated inactive form of GSK3β ser9 and as a result, proteasomal degradation of Mcl-1 occurred in both the cell lines. Here, we suggest that the apoptotic effect of DHP-8 in A375 and HepG2 cells was mediated by AKT and survivin pathways through SIRT1 activation. The involvement of DHP-8 in SIRT1 activation was further verified by co-treatment of nicotinamide with DHP-8 in both A375 and HepG2 cells. Overall, this study emphasizes the possible potential and therapeutic role of DHP-8 in skin and liver cancer.

Purpose of the Review: The 5-year survival rate of patients with pancreatic cancer (PanCA) has remained stagnant. Unfortunately, the incidence is almost equal to mortality rates. These facts underscore the importance of concerted efforts to understand the pathology of this disease. Deregulation of multiple signaling pathways involved in a wide variety of cellular processes including proliferation, apoptosis, invasion, and metastasis contribute not only to cancer development but also to therapeutic resistance. The purpose of this review is to summarize current understanding of etiological factors including emerging evidence on the role of infectious agents, factors associated with therapeutic resistance and therapeutic options., Recent Findings: The unique aspect of PanCA is "desmoplasia", a process that involves proliferation of stromal fibroblasts and collagen deposition in and around the filtrating cancer. Recent studies have identified pancreatic stellate cells (PSCs) as a potential source of such desmoplasia. Biphasic interactions between PSCs and cancer cells, endothelial cells, and/or myeloid derived suppressor cells in the tumor microenvironment contribute to pancreatic carcinogenesis., Summary: We summarize limitations of current therapeutic approaches and potential strategies to overcome these limitations using natural products including botanicals as adjuvant/neo-adjuvant for effective management of PanCA., Competing Interests: Conflict of interest statement: Authors declare no conflicts of interest.

Lack of effective options following failure to conventional chemotherapeutic agent such as Docetaxel (DX) is a major clinical challenge in the management of prostate cancer. These observations underscore the need for deciphering the underlying mechanism of DX resistance to enable the development of effective therapeutic approaches. We observed up regulation of the anti-apoptotic protein c-FLIP and its up stream regulators including receptor tyrosine kinase RON and transcription factor NFκB (p65) in tumors obtained from metastatic prostate cancer patients. We also observed significant downregulation of these molecules in prostate tumors isolated from patients treated with DX as first line therapy. Further, we identified the over the counter anti-inflammatory agent, Nexrutine (NX) suppresses c-FLIP protein levels, and expression in androgen-independent prostate cancer cells (PC-3). Remarkably, the observed decreased levels of c-FLIP were further reduced in combination with DX. Transient expression assays coupled with electrophoretic mobility shift and DNA affinity protein assay revealed that NX and DX suppresses c-FLIP promoter activity by preventing p65 binding. Notably, NX in combination with DX abolished binding of p65 to the c-FLIP promoter sequence containing NFκB binding sites. Biologically, these alterations resulted in reduced growth of PC-3 cells. Taken together, these observations suggest the utility of RON, p65, and c-FLIP as potential markers to predict response to DX treatment. Furthermore, our results also identified NX as an agent to potentiate the therapeutic response of DX by suppressing activation of c-FLIP and its upstream regulators., (© 2017 Wiley Periodicals, Inc.)

Two prominent features of tumors that contribute to oncogenic survival signaling are redox disruption, or oxidative stress phenotype, and high autophagy signaling, making both phenomena ideal therapeutic targets. However, the relationship between redox disruption and autophagy signaling is not well characterized and the clinical impact of reactive oxygen species (ROS)-generating chemotherapeutics on autophagy merits immediate attention as autophagy largely contributes to chemotherapeutic resistance. In this commentary we focus on melanoma, using it as an example to provide clarity to current literature regarding the roles of autophagy and redox signaling which can be applicable to initiation and maintenance of most tumor types. Further, we address the crosstalk between ROS and autophagy signaling during pharmacological intervention and cell fate decisions. We attempt to elucidate the role of autophagy in regulating cell fate following treatment with ROS-generating agents in preclinical and clinical settings and discuss the emerging role of autophagy in cell fate decisions and as a cell death mechanism. We also address technical aspects of redox and autophagy evaluation in experimental design and data interpretation. Lastly, we present a provocative view of the clinical relevance, emerging challenges in dual targeting of redox and autophagy pathways for therapy, and the future directions to be addressed in order to advance both basic and translational aspects of this field., (Copyright © 2016 Elsevier Inc. All rights reserved.)

There is an unmet need to develop new agents or strategies against therapy resistant pancreatic cancer (PanCA). Recent studies from our laboratory showed that STAT3 negatively regulates NF-κB and that inhibition of this crosstalk using Nexrutine® (Nx) reduces transcriptional activity of COX-2. Inhibition of these molecular interactions impedes pancreatic cancer cell growth as well as reduces fibrosis in a preclinical animal model. Nx is an extract derived from the bark of Phellodendron amurense and has been utilized in traditional Chinese medicine as antidiarrheal, astringent, and anti-inflammatory agent for centuries. We hypothesized that "Nx-mediated inhibition of survival molecules like STAT3 and NF-κB in pancreatic cancer cells will improve the efficacy of the conventional chemotherapeutic agent, gemcitabine (GEM)." Therefore, we explored the utility of Nx, one of its active constituents berberine and its derivatives, to enhance the effects of GEM. Using multiple human pancreatic cancer cells we found that combination treatment with Nx and GEM resulted in significant alterations of proteins in the STAT3/NF-κB signaling axis culminating in growth inhibition in a synergistic manner. Furthermore, GEM resistant cells were more sensitive to Nx treatment than their parental GEM-sensitive cells. Interestingly, although berberine, the Nx active component used, and its derivatives were biologically active in GEM sensitive cells they did not potentiate GEM activity when used in combination. Taken together, these results suggest that the natural extract, Nx, but not its active component, berberine, has the potential to improve GEM sensitivity, perhaps by down regulating STAT3/NF-κB signaling. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

The current standard of care for prostate cancer includes hormone therapy, radiation therapy and radical prostatectomy, each with its own set of undesirable side effects. In this regard there is an unmet need to develop strategies that can prevent or delay the development of clinical prostate cancer. One potential area involves the use of natural compounds involving botanicals. Along these lines we have found that Nexrutine ® , a dietary supplement derived from Phellodendron amurense bark extract, has prostate cancer prevention activity. The "extract" nature of this botanical, which constitutes a blend of several active protoberberine alkaloids, allows it to target several pathways deregulated in prostate cancer simultaneously. In this review, we will emphasize the prospective translational benefit of Nexrutine ® as a chemopreventive agent for prostate cancer management. The potential of Nexrutine ® was first identified and has subsequently been most exhaustively studied with reference to prostate cancer. Therefore the focus of this review is on the use of Nexrutine ® in prostate cancer. In addition we have summarized the emerging evidence regarding the use of Nexrutine ® in other tumor models to demonstrate the potential benefits of Nexrutine ® .

Novel agents are desperately needed for improving the quality of life and 5-year survival to more than 30% for metastatic castrate-resistant prostate cancer. Previously we showed that Nexrutine, Phellodendron amurense bark extract, inhibits prostate tumor growth in vitro and in vivo. Subsequently using biochemical fractionation we identified butanol fraction contributes to the observed biological activities. We report here that palmatine, which is present in the butanol fraction, selectively inhibits growth of prostate cancer cells without significant effect on non-tumorigenic prostate epithelial cells. By screening receptor tyrosine kinases in a protein kinase array, we identified ribosomal protein S6, a downstream target of p70S6K and the Akt/mTOR signaling cascade as a potential target. We further show that palmatine treatment is associated with decreased activation of NFκB and its downstream target gene FLIP. These events led to inhibition of invasion. Similar results were obtained using parent extract Nexrutine (Nx) suggesting that palmatine either in the purified form or as one of the components in Nx is a potent cytotoxic agent with tumor invasion inhibitory properties. Synergistic inhibition of rpS6/NFκB/FLIP axis with palmatine may have therapeutic potential for the treatment of prostate cancer and possibly other malignancies with their constitutive activation. These data support a biological link between rpS6/NFκB/FLIP in mediating palmatine-induced inhibitory effects and warrants additional preclinical studies to test its therapeutic efficacy., (© 2014 Wiley Periodicals, Inc.)

Two novel amphiphilic molecules were synthesized by the reaction between poly(ethylene glycol) methyl ether (mPEG) of different chain lengths and sodium-2-mercapto ethane sulfonate (mesna). Different techniques, such as surface tensiometry, conductometry, fluorescence spectroscopy, dynamic light scattering, UV-vis spectroscopy, transmission electron microscopy, and isothermal titration calorimetry were employed to investigate the self-assembly properties of the PEG-based single-tailed amphiphiles in aqueous buffer. Despite having so called polar tail the amphiphiles exhibit aggregate formation in aqueous buffer as well as in water. The shorter chain amphiphile was shown to form bilayer vesicles in contrast to small micelles by its longer chain counterpart. The helicity of the PEG chain was taken into consideration to interpret the difference in self-assembled microstructure formation. The thermodynamics of the self-assemblies were also thoroughly examined. The thermodynamic parameters clearly suggested that the hydrophobic interaction among the PEG chains is the main driving force for aggregate formation. The self-assembled microstructures were observed to be fairly stable with respect to increase of surfactant concentration, aging time and temperature., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Chronic inflammation is postulated to influence prostate cancer progression. Preclinical studies have claimed that inflammatory mediators are involved in prostate cancer development and therefore suggested these as attractive targets for intervention. However, among the many pro-inflammatory mediators, there is no consensus regarding the identity of the primary one(s). In clinical studies, chronic inflammation has been found in prostate tumor specimens, and tissues resected for treatment of benign prostatic hyperplasia (BPH). Although collective evidence from molecular, experimental and clinical data suggests that inflammation can contribute or promote prostate carcinogenesis, an etiologic link has not yet been established. Moreover, the role of chronic inflammation in the onset of castration resistant and metastatic disease is unclear. Therefore it is important to open a dialog regarding recent findings on how chronic inflammatory mediators contribute to prostate cancer progression, and their usefulness to prevent disease progression. In this commentary, we assess the current literature with respect to chronic inflammation as a potential initiator and promoter of prostate carcinogenesis and discuss the prospects for its potential clinical applications., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Ultraviolet C (UVC) irradiation (λ: 200-280 nm) causes release of several secretory cytokines responsible for inflammation. Our objective was to investigate whether inflammatory response was also induced in bystander cells. For this purpose, the conditioned medium containing the released factors from UVC irradiated A375 cells was used in this study to evaluate the expression of inflammatory markers, such as tumour necrosis factor alpha (TNFα), nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) and p38 mitogen-activated protein kinase (p38 MAPK) in its bystander cells. Inflammatory responses in bystander cells subjected to further irradiation by UVC or other damaging agent like H2O2 were also examined. It was observed that TNFα, NFκB and p38 MAPK were not induced in UVC-bystander cells, but their expression was suppressed in the UVC-bystander cells treated with UVC or H2O2. This lowering in inflammatory response might be due to smaller depletion in the reduced glutathione (GSH) content present in these treated bystander cells. The study indicated that UVC-induced bystander effect was an intrinsic protective response in cells, capable of suppressing inflammation induced in cells on exposure to damaging agents.

It appears that the story on vitamin E and its role in human health remains incomplete. It is apparent that vitamin E supplementation involves many variables, some of which include its uptake from the intestine, the preference for α-tocopherol, transport by tocopherol specific proteins and lipid transporters and the differential metabolism of different vitamin E isoforms. The fundamental differences within population genetics can have significant implications for the effect that dietary supplementation might have on human health. When evaluating the efficacy of vitamin E prophylactic or therapeutic use in previous and future studies, it is critical to consider dosage to be administered, form of vitamin E and source (such as whether from synthetic or purified from natural sources). Further studies are needed to determine the effects of all vitamin E isoforms on cell growth, tumorigenicity, to clarify its possible use as an adjuvant to existing chemotherapeutics. The Alpha-Tocopherol, Beta Carotene (ATBC) Cancer Prevention Study Group and Selenium and Vitamin E Cancer Prevention Trial (SELECT) studies along with the numerous studies of vitamin E should help guide the next chapter of vitamin E research., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Bystander effect is the communication of signals from irradiated to unexposed neighboring cells which is often mediated through factors released from irradiated cells. We have attempted to investigate whether UV-bystander phenomenon can modulate the sensitivity of A375 cells and its mechanism. For this purpose, the conditioned medium from UVC-irradiated cells, which contained these released factors, was used to treat non-exposed cells. These cells were then subsequently treated with UVC or another genotoxicant H2O2. Cell viability was determined by Trypan blue-exclusion assay, DNA damage by flow cytometry analysis, ROS production by flow cytometry and microscopic analysis. Lipid peroxidation and antioxidant defense were assayed biochemically. Our findings revealed that exposure of non-irradiated cells to these factors induced increased in SOD and catalase activities which reverted to normal levels by 8 h. During this period, the released factors-treated cells were resistant to killing by UVC or H2O2 and induced DNA damage and lipid peroxidation were also lowered. This protection from cell killing was not present 8 h after exposure to these released factors. Our results suggested UV-bystander effect increased viability of cells through induction of antioxidant defense. This indicated UV-bystander phenomenon triggers protective response in cells.

We derived V79(C) cells from V79 cell line through chronic oxidative stress by H2O2. These cells demonstrated transformation-like stable changes. Our objective was to see how V79(C) cells would respond to cisplatin treatment and also to understand the mechanism of cisplatin-resistance, because resistance towards various chemotherapeutic agents is major cause of concern in cancer therapeutics. The sensitivity to cisplatin in these cells was observed by comparing the viability with that of parental V79 cells from colonogenic assay. The role of apoptotic death was investigated microscopically by Hoechst staining and from nucleosomal ladder formation in agarose gel. Release of cytochrome c from the mitochondria was determined by Western blotting. Caspase 9 and caspase 3 activities were estimated through fluorimetric assay. We found that V79(C) cells exhibited lower sensitivity towards killing by cisplatin through suppression of apoptotic cell death. Quantifying the release of cytochrome c in the cytoplasm and assay of caspase 9 and caspase 3 activities revealed that cisplatin resistance was due to inhibition of caspase-dependent apoptotic death pathways. These findings may aid in understanding the mechanism of cisplatin resistance in tumors arising from oxidative stress. Exogenous caspases may facilitate apoptotic death to sensitize such resistant cells.

Extensive research has led to the firm conclusion that antioxidants protect cells from damage caused by oxidative stress and its associated pathological conditions including inflammation. It has also been established that inflammation is a precursor in neoplastic transformation of the prostate. Although, a vast body of experimental and clinical evidence shows efficacy of antioxidants as preventive strategies for prostate cancer, there is a lack of consistent agreement in outcomes especially from recent large-scale randomized clinical trials. Despite these concerns, our understanding of the preventive mechanisms as well as clinical efficacy and safety data indicate that novel antioxidant therapeutics still hold great promise for prostate cancer chemoprevention. We propose that for effective use of antioxidants for prostate cancer prevention, further high impact translational research is needed with special attention on selecting those patients who will benefit from such intervention. Therefore, it is important to validate predictive biomarkers from successful trials and combine this with knowledge of preclinical characterization of antioxidants (and combinations) that will eventually facilitate the development of 'personalized prostate cancer chemoprevention'. In this review, we briefly describe some common and emerging antioxidants that have shown benefits in preclinical and clinical settings. Above all, we focus on summarizing the progress we made thus far in prostate cancer chemoprevention using antioxidants, the heightened interest and challenges in the future., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Several acridine derivatives have been screened for their therapeutic potential and some are already established as antiprotozoan, antibacterial or anticancer agents. However, phenyl derivative at C-9 position of acridine had remained unexplored for their biological activity so far. In this report, we present our findings with 9-phenyl acridine (ACPH) as an anticancer agent. Both A375 and HeLa, two human cancer cell lines, were more sensitive to ACPH than normal cells namely human lymphocytes and also Chinese hamster V79 cells. ACPH also led to regression of tumour volume in mice. In A375 cells, we have shown that it caused DNA damage and blocked cell cycle progression at G(2)-M phase. Treatment with ACPH led to lowering of mitochondrial potential, upregulation of bax, release of cytochrome C and activation of caspase 3. As a new agent showing lower toxicity to normal cells and greater sensitivity towards cancerous cell line, ACPH shows promise as an effective cancer chemotherapeutic agent. ACPH treatment resulted in apoptotic death of cells through mitochondria-mediated caspase-dependent pathway.

The long-term environmental impact of municipal solid waste (MSW) landfilling is still under investigation due to the lack of detailed characterization studies. A MSW landfill site, popularly known as Dhapa, in the eastern fringe of the metropolis of Kolkata, India, is the subject of present study. A vast area of Dhapa, adjoining the current core MSW dump site and evolving from the raw MSW dumping in the past, is presently used for the cultivation of vegetables. The inorganic chemical characteristics of the MSW-contaminated Dhapa surface soil (covering a 2-km stretch of the area) along with a natural composite (geogenic) soil sample (from a small countryside farm), for comparison, were investigated using two complementary nondestructive analytical techniques, energy-dispersive X-ray fluorescence (EDXRF) for bulk analysis and low-Z (atomic number) particle electron probe X-ray microanalysis (low-Z particle EPMA) for single-particle analysis. The bulk concentrations of K, Rb, and Zr remain almost unchanged in all the soil samples. The Dhapa soil is found to be polluted with heavy metals such as Cu, Zn, and Pb (highly elevated) and Ti, Cr, Mn, Fe, Ni, and Sr (moderately elevated), compared to the natural countryside soil. These high bulk concentration levels of heavy metals were compared with the Ecological Soil Screening Levels for these elements (U.S. Environment Protection Agency) to assess the potential risk on the immediate biotic environment. Low-Z particle EPMA results showed that the aluminosilicate-containing particles were the most abundant, followed by SiO2, CaCO3-containing, and carbonaceous particles in the Dhapa samples, whereas in the countryside sample only aluminosilicate-containing and SiO2 particles were observed. The mineral particles encountered in the countryside sample are solely of geogenic origin, whereas those from the Dhapa samples seem to have evolved from a mixture of raw dumped MSW, urban dust, and other contributing factors such as wind, precipitation, weather patterns, farming, and water logging, resulting in their diverse chemical compositions and the abundant observation of carbonaceous species. Particles containing C and P were more abundant in the Dhapa samples than in the countryside soil sample, suggesting that MSW-contaminated soils are more fertile. However, the levels of particles containing potentially toxic heavy metals such as Cr, Mn, Ni, Cu, Zn, and/or Pb in the Dhapa samples were significant, corroborated by their high bulk concentration levels (EDXRF), causing deep concern for the immediate environment and contamination of the food chain through food crops.

Intravesical immunotherapy using attenuated bacillus Calmette-Guérin (BCG) strains and intravesical chemotherapy are the modalities most commonly used to treat intermediate- or high-risk patients with non-muscle invasive bladder cancer. BCG has been shown to decrease recurrence rates by up to 67% compared with tumor resection alone, but intensive BCG maintenance regimens are poorly tolerated in a large proportion of patients. Intravesical chemotherapy also decreases the risk of recurrence for these patients, but has diminished efficacy compared with BCG. If BCG dose reduction can be achieved with combined intravesical immunotherapy and chemotherapy, this regimen may improve compliance and thus optimize treatment for these patients by limiting side effects from BCG monotherapy, while at the same time improving oncologic efficacy via the separate anti-tumor mechanisms of these agents. The authors discuss the most recent data regarding combining these agents in an alternating or sequential regimen.

Acridines and their derivatives are well-known probes for nucleic acids as well as being relevant in the field of drug development to establish new chemotherapeutic agents. We have shown from molecular modelling studies that 9-phenyl acridine and some of its derivatives can act as inhibitors of topoisomerase I and thus have potential to act as anticancer agents. Rational design of new compounds for therapeutics requires knowledge about their structural stability and interactions with various cellular macromolecules. In this regard it is important to know how these molecules would interact with DNA. Here we report the interaction of 9-phenyl acridine (ACPH) with calf thymus DNA (CT-DNA) based on various biophysical and molecular modelling studies. Spectrophotometric studies indicated that ACPH binds to CT-DNA. DNA melting studies revealed that binding of ACPH to CT-DNA resulted in a small increase in melting temperature, which is unlikely in case of classical intercalator; rather, it indicates external binding. Viscosity measurements show that ACPH exhibits groove binding. Competitive binding of ACPH to CT-DNA pre-bound to ethidium bromide (EB) showed slow quenching. Measurement of the binding constant of ACPH by fluorescent intercalator displacement (FID) assay corroborated the notion that there was groove binding. Molecular modelling studies also supported this finding. Results indicate that binding of ACPH is through partial intercalation in the minor groove of DNA.

Our ability to detect and treat most primary cancers has improved dramatically given the advances in our understanding of cancer biology. However, with increased life expectancy and our inability to treat or cure advanced stages of cancers, the number of cancer-related deaths is expected to double in the next decade. Epidemiological studies suggest that dietary factors are an important aspect that influences cancer risk. Despite a lack of scientific evidence in most cases, cancer patients have whole-heartedly accepted the concept of "alternative medicine" using natural compounds and spent more than $1B a year on herbal supplements. Given the significant toxicity-associated problems with current long-term standard of care, scientifically validated natural supplements can serve as novel and effective alternative strategies for effective cancer management. We will discuss the utility of natural products in modulating critical signaling pathways for effective cancer prevention with special emphasis on prostate cancer and their potential translational benefit.

Prostate cancer is the second leading cause of cancer-related deaths in men in Western society. Epidemiological studies suggest that a reduced risk of cancer is associated with the consumption of a phytochemical-rich diet that includes fruits and vegetables. Strategies to delay clinically significant prostate cancer will have a tremendous impact in reducing the overall incidence of prostate cancer as well as improving quality of life for elderly men. Furthermore, the long latency involved in the development of clinically significant prostate cancer provides a plethora of opportunities for its management, especially using prevention approaches. Previous studies from our laboratory show that Nexrutine (bark extract from Phellodendron amurense) prevents prostate tumor development when given prior to the development of high-grade prostatic intraepithelial neoplasia in the transgenic adenocarcinoma of mouse prostate (TRAMP) model. In this study, we investigated the effect on the progression of established tumors in the TRAMP model by administering Nexrutine to 28-week-old TRAMP mice. Efficacy of Nexrutine was determined by histopathological evaluation of the prostate. Our data indicate that Nexrutine inhibited progression of prostate tumors that was correlated with tissue levels of transcription factors nuclear factor kappa B, cyclic-AMP response element-binding protein and phosphorylated CREB. Moreover, Nexrutine intervention resulted in a significant increase in the bone mineral density of the left femur diaphysis (p=0.009) and prevented the development of metastatic lesions. Nexrutine treatment also significantly (p=0.005) inhibited invasion of androgen-independent prostate cancer cells.

Chinese hamster V79 cells were conditioned by repeated treatment with low doses of hydrogen peroxide. After this treatment, the conditioned cells were compared to parental V79 cells with regard to different endpoints. It was found that, compared to parental cells, the conditioned cells tolerated low serum concentrations better, they suffered from higher levels of aneuploidy, and they showed enhanced antioxidant defense. When exposed to gamma-rays, they suffered from lipid peroxidation to a lesser extent, were more resistant to cell killing, exhibited higher mutation frequency at the HGPRT locus, and showed lower frequency of apoptosis. These cells also induced antioxidant enzymes in response to gamma-ray exposure that differently was from than the parental cells. Overall, the data suggest a stable adaptive response in the conditioned cells.