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Most of the human cancers are dependent on telomerase to extend the telomeres. But ∼10% of all cancers use a telomerase-independent, homologous recombination mediated pathway called alternative lengthening of telomeres (ALT). Due to the poor prognosis, ALT status is not being considered yet in the diagnosis of cancer. No such specific treatment is available to date for ALT positive cancers. ALT positive cancers are dependent on replication stress to deploy DNA repair pathways to the telomeres to execute homologous recombination mediated telomere extension. SMARCAL1 (SWI/SNF related, matrix-associated, actin-dependent regulator of chromatin, subfamily A-like 1) is associated with the ALT telomeres to resolve replication stress thus providing telomere stability. Thus, the dependency on replication stress regulatory factors like SMARCAL1 made it a suitable therapeutic target for the treatment of ALT positive cancers. In this study, we found a significant downregulation of SMARCAL1 expression by stabilizing the G-quadruplex (G4) motif found in the promoter of SMARCAL1 by potent G4 stabilizers, like TMPyP4 and BRACO-19. SMARCAL1 downregulation led toward the increased localization of PML (promyelocytic leukemia) bodies in ALT telomeres and triggered the formation of APBs (ALT-associated promyelocytic leukemia bodies) in ALT positive cell lines, increasing telomere replication stress and DNA damage at a genomic level. Induction of replication stress and hyper-recombinogenic phenotype in ALT positive cells mediated by G4 stabilizing molecules already highlighted their possible application as a new therapeutic window to target ALT positive tumors. In accordance with this, our study will also provide a valuable insight toward the development of G4-based ALT therapeutics targeting SMARCAL1.

Innate lymphoid cells are a mixed population of cells and critical regulators of our innate immune system. According to recent scientific literature, tissue resident innate lymphoid cell subtype 2 has been recognized as an important player of type 2 inflammatory responses, involved in different human malignancies like pancreatic, lung, acute myeloid leukemia, gastrointestinal tract cancer, etc. The current reports have revealed that, among the three main ILC sub types, subtype 2 (ILC 2), as the key regulator of initiating the type 2 inflammatory responses at the tumor microenvironment (TME). This activation of ILC-2 is a very important step for the specific downstream functioning of ILC-2. Priming of ILC-2 with different chemokines involves different cytokine secretion from the activated ILC-2 like IL-4, IL-5, IL-13, IL-9 which induce type 2 inflammatory responses involved in the complex interaction with other immune cells like NK cell, Cytotoxic T cell, MDSC and T reg cell. At the initial stage, ILC-2 activation through IL-33 may induce the anti-tumorigenic effect mediated by ILC-2/eosinophil axis. However, it is also evident that PDG2 (Prostaglandin D2)-mediated activation of ILC-2 induces the ILC-2/MDSC immune suppressive pro-tumorigenic niche at the TME. Here, in this review, we have summarized the function of ILC-2 on cancer immunity based on recent scientific work which indicates ILC-2 plays a dual role and orchestrates the immune responses toward type 2 immunity in different cancer settings.

HDAC9 is a histone deacetylase enzyme belonging to the class IIa of HDACs which catalyses histone deacetylation. HDAC9 inhibit cell proliferation by repairing DNA, arresting the cell cycle, inducing apoptosis, and altering genetic expression. HDAC9 plays a significant part in human physiological system and are involved in various type of diseases like cancer, diabetes, atherosclerosis and CVD, autoimmune response, inflammatory disease, osteoporosis and liver fibrosis. This review discusses the role of HDAC9 in different diseases and structure-activity relationships (SARs) of various hydroxamate and non-hydroxamate-based inhibitors. SAR of compounds containing several scaffolds have been discussed in detail. Moreover, structural requirements regarding the various components of HDAC9 inhibitor (cap group, linker and zinc-binding group) has been highlighted in this review. Though, HDAC9 is a promising target for the treatment of a number of diseases including cancer, a very few research are available. Thus, this review may provide useful information for designing novel HDAC9 inhibitors to fight against different diseases in the future., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

In the past decades, for the intermediate or advanced cancerous stages, preclinical and clinical applications of nanomedicines in cancer theranostics have been extensively studied. Nevertheless, decreased specificity and poor targeting efficiency with low target concentration of theranostic are the major drawbacks of nanomedicine in employing clinical substitution over conventional systemic therapy. Consequently, ligand decorated nanocarrier-mediated targeted drug delivery system can transcend the obstructions through their enhanced retention activity and increased permeability with effective targeting. The highly efficient and specific nanocarrier-mediated ligand-based active therapy is one of the novel and promising approaches for delivery of the therapeutics for different cancers in recent years to restrict various cancer growth in vivo without harming healthy cells. The article encapsulates the features of nanocarrier-mediated ligands in augmentation of active targeting approaches of various cancers and summarizes ligand-based targeted delivery systems in treatment of cancer as plausible theranostics., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Several HER2-specific peptides are being continuously explored to find a candidate with suitable pharmacokinetic properties for development of effective radiopharmaceutical that can find applications for clinical screening of breast cancer patients. In the present work with an aim of preparing a radiopeptide with improved metabolic stability and in vivo pharmacokinetic performance we modified our previously reported [ 177 Lu]DOTA-L-A9 peptide. Here we designed an 'inverso' peptide with all d-amino acids and a 'retro-inverso' peptide where sequence of d-amino acids was reversed. Higher secondary structure stabilization of retro- inverso A9 variant compared to inverso A9 peptide was evident by circular dichroism studies. The two radiopeptides [ 177 Lu]DOTA-D-A9 and [ 177 Lu]DOTA-rD-A9 exhibited significantly improved in vivo metabolic stability over the original l-peptide. The retro-inverso variant, [ 177 Lu]DOTA-rD-A9 demonstrated better pharmacokinetic behavior with significantly higher tumor uptake than the inverso peptide, [ 177 Lu]DOTA-D-A9 and the original peptide, [ 177 Lu]DOTA-L-A9. In the present case of A9 peptide, reversal of the peptide sequence of d-amino acids boosted the uptake and retention of radioactivity in HER2-positive tumor. The present study can thus guide the design and development of newer and improved versions of peptides., 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 © 2023 Elsevier Inc. All rights reserved.)

Aspartic acid is a non-essential amino acid obtained in the neuroendocrine tissues of vertebrates and invertebrates. Aspartic acid, a major excitatory neurotransmitter in the mammalian central nervous system, plays a key role in memory and acts in many other normal and abnormal physiological processes. In this work, we have developed an efficient chemosensor (PCF) based on the pyridine-carbazole moiety for the differential detection of aspartic acid in biological systems. PCF has a strong binding affinity towards aspartic acid, with a detection limit in the nanomolar range. The binding stoichiometry of aspartic aid and PCF was obtained as 1 : 1 from a Jobs plot analysis. Furthermore, the efficacy of PCF has been successfully demonstrated in in vitro experiments in MCF-7 breast cancer cells.

Cancer pathologies are associated with the unfolding and aggregation of most recurring mutations in the DNA Binding Domain (DBD) of p53 that coordinate the destabilization of protein. Substitution at the 175th codon with arginine to histidine (R175H, a mutation of large to small side-chain amino acid) destabilizes the DBD by 3 kcal/mol and triggers breasts, lung cancer, etc. Stabilizing the p53 mutant by small molecules offers an attractive drug-targeted anti-cancer therapy. The thiosemicarbazone (TSC) molecules NPC and DPT are known to act as zinc-metallochaperones to reactivate p53R175H. Here, a combination of LESMD simulations for 10 TSC conformations with a p53R175H receptor, single ligand-protein conformation MD, and ensemble docking with multiple p53R175H conformations observed during simulations is suggested to identify the potential binding site of the target protein in light of their importance for the direct TSC - p53R175H binding. NPC binds mutant R175H in the loop region L2-L3, forming pivotal hydrogen bonds with HIS175, pi‑sulfur bonds with TYR163, and pi-alkyl linkages with ARG174 and PRO190, all of which are contiguous to the zinc-binding native site on p53DBD. DPT, on the other hand, was primarily targeting alternative binding sites such as the loop-helix L1/H2 region and the S8 strand. The similar structural characteristics of TSC-bound p53R175H complexes with wild-type p53DBD are thought to be attributable to involved interactions that favour binding free energy contributions of TSC ligands. Our findings may be useful in the identification of novel pockets with druggable properties., Competing Interests: Declaration of Competing Interest There are no conflicts to declare., (Copyright © 2023. Published by Elsevier B.V.)

It is reasonable to think that cancer patients undergoing chemotherapy or immunotherapy may have a more aggressive course if they are positive for the novel coronavirus disease. Their compulsive condition requires investigation into effective drugs. We applied computational techniques to a series of compounds known for restoring the function of p53 cancer mutant p53 R175H and p53 G245S . Two potent inhibitors, 1-(3-chlorophenyl)-3-(1, 3 -thiazol-2-yl) urea (CTU, PubChem NSC321792) with the highest binding affinity -6.92 kcal/mol followed by a thiosemicarbazone compound N'-(1-(Pyridin-2-yl)ethylidene) azetidine - 1 -carbothiohydrazide (NPC, PubChem NSC319726) with -6.75 kcal/mol were subjected to Molecular Dynamics simulation with receptor binding domain (RBD) and compared with control ligand dexamethasone. In particular, CTU adheres to pocket 1 with an average free energy of binding -21.65 ± 2.89 kcal/mol at the RBD - angiotensin-converting enzyme 2 binding region with the highest frequency of amino acid residues after reaching a local equilibrium in 100 ns MD simulation trajectory. A significant enthalpy contribution from the independent simulations unfolds the possibility of dual binding sites for NPC as shifted pocket 1 (-15.59 ± 5.98 kcal/mol) and pocket 2 (-18.90 ± 5.02 kcal/mol). The obtained results for these two compounds are in good agreement with dexamethasone (-18.45   ± 2.42 kcal/mol). Taken together our findings could facilitate the discovery of small molecules that restore the function of p53 cancer mutants newly against COVID-19 in cancer patients.Communicated by Ramaswamy H. Sarma.

Altered RGS5-associated intracellular pericyte signaling and its abnormal crosstalk with endothelial cells (ECs) result chaotic tumor-vasculature, prevent effective drug delivery, promote immune-evasion and many more to ensure ultimate tumor progression. Moreover, the frequency of lethal-RGS5 high  pericytes within tumor was found to increase with disease progression, which signifies the presence of altered cell death pathway within tumor microenvironment (TME). In this study, we checked whether and how neem leaf glycoprotein (NLGP)-immunotherapy-mediated tumor growth restriction is associated with modification of pericytes' signaling, functions and its interaction with ECs. Analysis of pericytes isolated from tumors of NLGP treated mice suggested that NLGP treatment promotes apoptosis of NG2 + RGS5 high -fuctionally altered pericytes by downregulating intra-tumoral TGFβ, along with maintenance of more matured RGS5 neg  pericytes. NLGP-mediated inhibition of TGFβ within TME rescues binding of RGS5 with Gαi and thereby termination of PI3K-AKT mediated survival signaling by downregulating Bcl2 and initiating pJNK mediated apoptosis. Limited availability of TGFβ also prevents complex-formation between RGS5 and Smad2 and rapid RGS5 nuclear translocation to mitigate alternate immunoregulatory functions of RGS5 high  tumor-pericytes. We also observed binding of Ang1 from pericytes with Tie2 on ECs in NLGP-treated tumor, which support re-association of pericytes with endothelium and subsequent vessel stabilization. Furthermore, NLGP-therapy- associated RGS5 deficiency relieved CD4 +  and CD8 + T cells from anergy by regulating 'alternate-APC-like' immunomodulatory characters of tumor-pericytes. Taken together, present study described the mechanisms of NLGP's effectiveness in normalizing tumor-vasculature by chiefly modulating pericyte-biology and EC-pericyte interactions in tumor-host to further strengthen its translational potential as single modality treatment., (© 2022 Federation of American Societies for Experimental Biology.)

In epithelia, normal cells recognize and extrude out newly emerged transformed cells by competition. This process is the most fundamental epithelial defence against cancer, whose occasional failure promotes oncogenesis. However, little is known about what factors determine the success or failure of this defence. Here we report that mechanical stiffening of extracellular matrix attenuates the epithelial defence against HRas V12 -transformed cells. Using photoconversion labelling, protein tracking, and loss-of-function mutations, we attribute this attenuation to stiffening-induced perinuclear sequestration of a cytoskeletal protein, filamin. On soft matrix mimicking healthy epithelium, filamin exists as a dynamically single population, which moves to the normal cell-transformed cell interface to initiate the extrusion of transformed cells. However, on stiff matrix mimicking fibrotic epithelium, filamin redistributes into two dynamically distinct populations, including a new perinuclear pool that cannot move to the cell-cell interface. A matrix stiffness-dependent differential between filamin-Cdc42 and filamin-perinuclear cytoskeleton interaction controls this distinctive filamin localization and hence, determines the success or failure of epithelial defence on soft versus stiff matrix. Together, our study reveals how pathological matrix stiffening leads to a failed epithelial defence at the initial stage of oncogenesis., (© 2022. The Author(s).)

Cell cycle kinases represent an important component of the cell machinery that controls signal transduction involved in cell proliferation, growth, and differentiation. Nek2 is a mitotic Ser/Thr kinase that localizes predominantly to centrosomes and kinetochores and orchestrates centrosome disjunction and faithful chromosomal segregation. Its activity is tightly regulated during the cell cycle with the help of other kinases and phosphatases and via proteasomal degradation. Increased levels of Nek2 kinase can promote centrosome amplification (CA), mitotic defects, chromosome instability (CIN), tumor growth, and cancer metastasis. While it remains a highly attractive target for the development of anti-cancer therapeutics, several new roles of the Nek2 enzyme have recently emerged: these include drug resistance, bone, ciliopathies, immune and kidney diseases, and parasitic diseases such as malaria. Therefore, Nek2 is at the interface of multiple cellular processes and can influence numerous cellular signaling networks. Herein, we provide a critical overview of Nek2 kinase biology and discuss the signaling roles it plays in both normal and diseased human physiology. While the majority of research efforts over the last two decades have focused on the roles of Nek2 kinase in tumor development and cancer metastasis, the signaling mechanisms involving the key players associated with several other notable human diseases are highlighted here. We summarize the efforts made so far to develop Nek2 inhibitory small molecules, illustrate their action modalities, and provide our opinion on the future of Nek2-targeted therapeutics. It is anticipated that the functional inhibition of Nek2 kinase will be a key strategy going forward in drug development, with applications across multiple human diseases.

Porphyrins are used for cancer diagnostic and therapeutic applications, but the mechanism of how porphyrins accumulate in cancer cells remains elusive. Knowledge of how porphyrins enter cancer cells can aid the development of more accurate cancer diagnostics and therapeutics. To gain insight into porphyrin uptake mechanisms in cancer cells, we developed a flow cytometry assay to quantify cellular uptake of meso-tetra (4-carboxyphenyl) porphyrin (TCPP), a porphyrin that is currently being developed for cancer diagnostics. We found that TCPP enters cancer cells through clathrin-mediated endocytosis. The LDL receptor, previously implicated in the cellular uptake of other porphyrins, only contributes modestly to uptake. We report that TCPP instead binds strongly ( K D = 42 nM ) to CD320, the cellular receptor for cobalamin/transcobalamin II (Cbl/TCN2). Additionally, TCPP competes with Cbl/TCN2 for CD320 binding, suggesting that CD320 is a novel receptor for TCPP. Knockdown of CD320 inhibits TCPP uptake by up to 40% in multiple cancer cell lines, including lung, breast, and prostate cell lines, which supports our hypothesis that CD320 both binds to and transports TCPP into cancer cells. Our findings provide some novel insights into why porphyrins concentrate in cancer cells. Additionally, our study describes a novel function for the CD320 receptor which has been reported to transport only Cbl/TCN2 complexes., (© 2021 Federation of American Societies for Experimental Biology.)

Objective: A DNA intercalating agent reversibly stacks between the adjacent base pairs of DNA and thus is expected to exhibit preferential localization in the tumorous lesions as tumors are associated with enhanced DNA replication. Therefore, radiolabeled DNA intercalators are supposed to have potential to be used in targeted tumor therapy. Working in this direction, an attempt was made to radiolabel 9-aminoacridine, a DNA intercalator, with 177 Lu, one of the most useful therapeutic radionuclides, and study the potential of 177 Lu-acridine in targeted tumor therapy. Experiments . 9-Aminoacridine was coupled with p -NCS-benzyl-DOTA to facilitate radiolabeling, and the conjugate was radiolabeled with 177 Lu. Different reaction parameters were optimized in order to obtain 177 Lu-acridine complex with maximum radiochemical purity. In vitro stability of the radiolabeled complex was studied in normal saline and human blood serum. Biological behavior of the radiolabeled agent was studied both in vitro and in vivo using the Raji cell line and fibrosarcoma tumor-bearing Swiss mice, respectively., Results: 177 Lu-acridine complex was obtained with ~100% radiochemical purity under the optimized reaction conditions involving incubation of 1.5 mg/mL of ligand with 177 Lu (1 mCi, 37 MBq) at 100°C at pH ~5 for 45 minutes. The complex maintained a radiochemical purity of >85% in saline at 6 d and >70% in human serum at 2 d postpreparation. In vitro cellular study showed uptake of the radiotracer (5.3 ± 0.13%) in the Raji cells along with significant cytotoxicity (78.06 ± 2.31% after 6 d). Biodistribution study revealed considerable accumulation of the radiotracer in tumor 9.98 ± 0.13 %ID/g within 1 h postadministration and retention therein till 6 d postadministration 4.00 ± 0.16 %ID/g with encouraging tumor to nontarget organ uptake ratios., Conclusions: The present study, although preliminary, indicates the potential of 177 Lu-acridine and thus radiolabeled DNA intercalators in targeted tumor therapy. However, further detailed evaluation is required to explore the actual potential of such agents in targeted tumor therapy., Competing Interests: The authors declare that there is no conflict of interest regarding publication of the present work., (Copyright © 2020 Subhajit Ghosh et al.)

Chronic exposure of glucose rich environment creates several physiological and pathophysiological changes. There are several pathways by which hyperglycemia exacerbate its toxic effect on cells, tissues and organ systems. Hyperglycemia can induce oxidative stress, upsurge polyol pathway, activate protein kinase C (PKC), enhance hexosamine biosynthetic pathway (HBP), promote the formation of advanced glycation end-products (AGEs) and finally alters gene expressions. Prolonged hyperglycemic condition leads to severe diabetic condition by damaging the pancreatic β-cell and inducing insulin resistance. Numerous complications have been associated with diabetes, thus it has become a major health issue in the 21st century and has received serious attention. Dysregulation in the cardiovascular and reproductive systems along with nephropathy, retinopathy, neuropathy, diabetic foot ulcer may arise in the advanced stages of diabetes. High glucose level also encourages proliferation of cancer cells, development of osteoarthritis and potentiates a suitable environment for infections. This review culminates how elevated glucose level carries out its toxicity in cells, metabolic distortion along with organ dysfunction and elucidates the complications associated with chronic hyperglycemia., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

The structural differences among different G-quadruplexes provide an opportunity for site-specific targeting of a particular G-quadruplex structure. However, majority of G-quadruplex ligands described thus far show little selectivity among different G-quadruplexes. In this work, we delineate the design and synthesis of a crescent-shaped thiazole peptide that preferentially stabilizes c-MYC quadruplex over other promoter G-quadruplexes and inhibits c-MYC oncogene expression. Biophysical analysis such as Förster resonance energy transfer (FRET) melting and fluorescence spectroscopy show that the thiazole peptide TH3 can selectively interact with the c-MYC G-quadruplex over other investigated G-quadruplexes and duplex DNA. NMR spectroscopy reveals that peptide TH3 binds to the terminal G-quartets and capping regions present in the 5'- and 3'-ends of c-MYC G-quadruplex with a 2:1 stoichiometry; whereas structurally related distamycin A is reported to interact with quadruplex structures via groove binding and end stacking modes with 4:1 stoichiometry. Importantly, qRT-PCR, western blot and dual luciferase reporter assay show that TH3 downregulates c-MYC expression by stabilizing the c-MYC G-quadruplex in cancer cells. Moreover, TH3 localizes within the nucleus of cancer cells and exhibits antiproliferative activities by inducing S phase cell cycle arrest and apoptosis.

Change in cellular pH due to onset of certain malfunctions needs to be tracked quickly so that treatment to cure such incidents may be started immediately. For example, microenvironment of a developing tumor is acidic due to high metabolic rate as well as low oxygen supply. Hence biomarkers that can sharply sense transition in pH could be of great use in the early detection of tumor formation. In the present work, a unique pH sensitive non-cytotoxic gold nanocluster based probe has been synthesized to precisely detect sharp change in biological pH. The gold nanoclusters were coated with dihydrolipoic acid incorporated γ-cyclodextrins. Measurements with steady state fluorometric changes reveal the sensibility of the probes through obvious wavelength shift depending on the changes in the microenvironment. The nanocluster based probe has been successfully applied to detect cancer cells with high precision., From the Clinical Editor: Biomarkers sensitive to physiological environment have extensive uses in nanomedicines. pH sensitive ultrasmall gold nanoclusters coated with dihydrolipoic acid incorporated γ-cyclodextrins indicate Changes in cellular pH, therefore certain malfunctions. The new biomarker could be useful to detect tumor calls., (Copyright © 2016 Elsevier Inc. All rights reserved.)

With the existing knowledge of ATM's role in therapeutic resistance, the present study aimed at identifying the molecular mechanisms that influence ATM to oscillate between chemoresistance and chemosensitivity. We observed that the redox status of tumors functions as a major determinant of ATM-dependent 'resistance-to-apoptosis' molecular switch. At a low reactive oxygen species (ROS) condition during genotoxic insult, the ATM/sumoylated-IKKγ interaction induced NFκB activation that resisted JNK-mediated apoptosis, whereas increasing cellular ROS restored ATM/JNK apoptotic signaling. A search for the upstream missing link revealed that high ROS induces oxidation and ubiquitin-mediated degradation of PIASγ, thereby disrupting PIASγ-IKKγ cross talk, a pre-requisite for IKKγ sumoylation and subsequent NFκB activation. Interruption in the PIASγ-mediated resistance pathway channels ATM signaling toward ATM/JNK pro-death circuitry. These in vitro results also translated to sensitive and resistant tumor allograft mouse models in which low ROS-induced resistance was over-ruled in PIASγ knockout tumors, while its overexpression inhibited high ROS-dependent apoptotic cues. Cumulatively, our findings identified an unappreciated yet critical combinatorial function of cellular ROS and PIASγ in regulating ATM-mediated chemosensitization of resistant tumors. Thus, therapeutic strategies employing ROS upregulation to inhibit PIASγ during genotoxic therapy may, in future, help to eliminate the problems of NFκB-mediated tumor drug resistance.

Chemotherapy remains the core of anticancer treatment. However, despite the tremendous strides made in the development of targeted anticancer therapies, emergence of resistance to chemotherapeutic drugs is still a major obstacle in the successful management of resistant tumours. Therefore, profound investigation into the in-depth molecular mechanisms of drug resistance is essential and may hopefully translate into effective therapies that can flip the switch from drug resistance to susceptibility. Mechanistically, resistance phenomena may be explained by (i) overexpression of drug efflux pumps, (ii) enhanced drug detoxification, (iii) rapid DNA repair efficiency, (iv) defects in apoptosis regulation, and (v) active cell survival signals. Several adverse effects associated with multidrug resistance and the need for safe multi-targeted anticancer drugs instigated the use of the phytochemical, curcumin, the yellow pigment of the spice turmeric, which has pleotropic activities. We performed a structured literature review using PubMed and Medline searches with secondary review of cited publications, identifying studies on the role of curcumin in conquering drug resistance in cancer. This review describes how curcumin sensitizes cancer cells through regulation of multiple multidrug resistance pathways, thus employing one drug for multiple targets. Curcumin helps the cancer cells to regain their 'forgotten' apoptosis, modulates drug-target interaction at different levels, restrains survival pathways when their proteins are overexpressed, and finds an alternate way to carry forward the process of sensitization of different resistant tumours. Additionally, the review dissects the role of curcumin, if any, in targeting the major culprit of drug resistance, cancer stem cells (CSC), thereby circumventing resistance. Taken together, this review strongly suggests that curcumin is a promising chemosensitizing agent and that the unique properties of curcumin may be exploited for successful management of resistant tumours.

TAMs, present in the tumor microenvironment, play an immunosuppressive role, leading to tumor progression and metastasis. Recently, numerous attempts have been made to switch immunosuppressive TAMs into an immunostimulatory type. Previously, we showed that a copper chelate, viz., copper N-(2-hydroxy acetophenone) glycinate [CuNG], can reprogram TAMs toward the proimmunogenic type to mount an antitumor immune response, but the underlying molecular mechanisms of skewing TAMs toward the proimmunogenic type remain elusive. Herein, we tried to explore the signaling mechanisms responsible for the reprogramming of TAMs. We observed that CuNG-induced ROS generation triggers activation of two MAPKs, i.e., p38MAPK and ERK1/2, and also causes up-regulation of intracellular glutathione. Furthermore, activation of p38 MAPK up-regulated the initial IL-12 production and the activation of ERK1/2 in tandem with GSH, found responsible for IFN-γ production by TAMs. This IFN-γ, in turn, prolonged IL-12 production and down-regulated TGF-β production and thus, plays the decisive role in CuNG-mediated reprogramming of regulatory cytokine production by TAMs. Our work highlights that ROS-mediated activation of MAPKs can convert suppressive macrophages toward the proimmunogenic type. Thus, the present study opens the possibility of targeting TAMs by the use of redox-active compounds for designing a novel, therapeutic strategy against cancer.

Tumors are multifaceted; in fact, numerous things happen in synchrony to enable tumor promotion and progression. Any type of cancer is associated with the modification of 300-500 normal genes and characterized by the deregulation of cell signaling pathways at multiple steps leading to cancer phenotype. Thus a proper management of tumorigenesis requires the development of multi-targeted therapies. Several adverse effects associated with present day cancer therapies and the thirsts for multi-targeted safe anticancer drug instigate the use of natural polyphenol, curcumin. It appears to involve a blend of anti-carcinogenic, pro-apoptotic, anti-angiogenic, anti-metastatic, immunomodulatory and antioxidant activities. Also the molecular mechanisms implicated for the pleotropic activities of curcumin are diverse and seem to involve a combination of cell signaling pathways at multiple levels of tumorigenesis. Being a potent scavenger of reactive oxygen species, curcumin also ameliorates systemic toxicity in tumor-bearer. Taken together, by placing particular emphasis on molecular basis of tumor promotion and progression this review summarizes the anti-cancer properties of curcumin that may be exploited for successful clinical cancer prevention.

With phytochemicals executing a plethora of anti-tumor mechanisms, targeting the 'guardian angel' p53 appears to be a critical strategy to energize the process of cancer therapeutics. Regulation of anti-tumor p53 functions by dietary plant polyphenols particularly black tea and its active component theaflavins has gained immense recognition from the point of view of both efficacy and safety. This review highlights the complexities of p53 functions, molecular mechanisms of its inactivation in cancer, and therapeutic strategies for rescuing p53 dysfunction in tumors using theaflavins. It describes how theaflavins, by steering a single molecular target - p53, regulate multiple hallmarks of carcinogenesis i.e., tumor glycolysis, angiogenesis, metastasis, apoptosis and drug resistance. Additionally, considering the rising of the current concept of cancer stem cells (CSCs), the sole participant in tumor evolution, the review discusses about the possible role of theaflavin-p53 cross talk in targeting CSCs. Such attempts to target the complexities of p53 functions during neogenesis will be of immense help in developing a "new" strategy for successful cancer prevention and therapy by theaflavins.

Despite major advances in understanding the mechanisms of tumor immunity, its successful translation into effective tumor immunotherapy is hindered by the ability of tumors to foster a tolerant microenvironment and to activate a plethora of immunosuppressive mechanisms. Among different strategies employed by tumors to thwart immune responses, shedding of immunosuppressive molecules, such as sialic acid-containing glycosphingolipids, gangliosides, by the tumor is one important strategy. Aberrant and elevated expression of gangliosides has been demonstrated on the surface of cancer cells. Here we discuss about the molecular mechanisms underneath the contribution of tumor gangliosides in targeting multiple steps of T cell response. We shall also underscore the contribution of T-regulatory, NK and dendritic cells in this immunosuppressive network. Inhibitory effects of gangliosides ultimately converge to T cell apoptosis in receptor-dependent and -independent manners via IL-2 deprivation, ROS production, cytochrome c release, NFkappaB inhibition and caspase activation. Current wealth of information promises a future scenario in which synchronized blockade of immunosuppressive mechanisms and removal of inhibitory signals might be effective in overcoming immunological tolerance and promoting tumor regression.

Tumor-site-specific delivery of anti-cancer drugs remains one of the most prevailing problems in cancer treatment. While conventional means of chemo-delivery invariably leave different degrees of side-effects on healthy tissues, in recent times, intelligent chemical designs have been exploited to reduce the cross-consequences. In particular, the strategies involving superparamaganetic nanoparticles with surface assembled oligonucleotides as therapeutic carrier have raised affirmative promises. Process is designed in such a way that the therapeutic molecules are released preferentially at target site as the complementary oligonucleotide chains dissociate over the heat generated by the nanoparticles under the excitation of low frequency electromagnetic energy. In spite of the preliminary demonstrations, analytical comprehension of the entire process especially on the purview of non-trivial interactions between stochastic phase-transition phenomena of oligonucleotide chains and hierarchical organization of in vivo transport processes remains unknown. Here, we propose an integrated computational predictive model to interpret the efficacy of drug delivery in the aforementioned process. The basic physics of heat generation by superparamagnetic nanoparticles in presence of external electromagnetic field has been coupled with transient biological heat transfer model and the statistical mechanics based oligonucleotide denaturation dynamics. Conjunctionally, we have introduced a set of hierarchically appropriate transport processes to mimic the in vivo drug delivery system. The subsequent interstitial diffusion and convection of the various species involved in the process over time was simulated assuming a porous media model of the carcinoma. As a result, the model predictions exhibit excellent congruence with available experimental results. To delineate a broader spectrum of a priori speculations, we have investigated the effects of different tunable parameters such as magnetizing field strength, nanoparticle size, diffusion coefficients, porous media parameters and different oligonucleotide sequences on temperature rise and site-specific drug release. The proposed model, thus, provides a generic framework for the betterment of nanoparticle mediated drug delivery, which is expected to impart significant impact on cancer therapy., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Introduction: Porphyrin and its derivatives exhibit inherent affinity for localization in tumors. Hence, porphyrin derivatives radiolabeled with suitable therapeutic radionuclides could be envisaged as potential agents for targeted tumor therapy. In this direction, a water-soluble porphyrin derivative, viz., 5,10,15,20-tetrakis[4-carboxymethyleneoxyphenyl]porphyrin was synthesized in-house and radiolabeled with (177)Lu with an aim to prepare an agent for targeted tumor therapy. (177)Lu is an attractive radionuclide for the development of targeted radiotherapeutic agents owing to its suitable decay characteristics [T(1/2)=6.73 d, E(beta(max))=0.49 MeV, Egamma=208 keV (11%)], comparatively longer half-life and ease of production with high specific activity., Methods: (177)Lu was produced by irradiation of enriched Lu(2)O(3) (64.3% (176)Lu) at a thermal neutron flux of 1x10(14) n/cm(2).s for 14 d. The porphyrin was coupled to a suitable chelator, namely, p-aminobenzyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid for complexation with (177)Lu. The radiolabeling was achieved by incubating 50 microg of the conjugate with (177)LuCl(3) (200 ng Lu) in acetate buffer (pH approximately 5) at 50 degrees C for 1 h. The radiolabeled conjugate was characterized by high-performance liquid chromatography and its biological efficacy was studied in Swiss mice bearing fibrosarcoma tumors., Results: (177)Lu was obtained with a specific activity of approximately 550 TBq/g and radionuclidic purity of 99.98%. The (177)Lu-labeled porphyrin conjugate was obtained with 99% radiochemical purity and it exhibited good in vitro stability. Biodistribution studies revealed good tumor uptake (2.01% IA/g) within 3 h post injection (p.i.) with >94% injected activity exhibiting renal clearance. No significant accumulation of activity was observed in any of the vital organs/tissue. The tumor/blood and tumor/muscle ratios were 2.89 and 16.80, respectively, at 3 h p.i. and further increased till 2 days p.i. up to which the studies continued. Serial scintigraphic images recorded using a gamma camera exhibited significant accumulation of activity in tumor over background at 3 days p.i., and the activity was observed to be retained in the tumor till 14 d. Preliminary efficacy studies carried out in Swiss mice bearing fibrosarcoma tumors showed significant regression of the tumor growth in the treated animals., Conclusion: Bioevaluation and preliminary tumor regression studies provide supportive evidences toward the possible potential of the (177)Lu-labeled porphyrin for targeted tumor therapy., (Copyright 2010 Elsevier Inc. All rights reserved.)

Immune dysfunction is well documented during tumor progression and likely contributes to tumor immune evasion. CD8(+) cytotoxic T lymphocytes (CTLs) are involved in antigen-specific tumor destruction and CD4(+) T cells are essential for helping this CD8(+) T cell-dependent tumor eradication. Tumors often target and inhibit T-cell function to escape from immune surveillance. This dysfunction includes loss of effector and memory T cells, bias towards type 2 cytokines and expansion of T regulatory (Treg) cells. Curcumin has previously been shown to have antitumor activity and some research has addressed the immunoprotective potential of this plant-derived polyphenol in tumor-bearing hosts. Here we examined the role of curcumin in the prevention of tumor-induced dysfunction of T cell-based immune responses. We observed severe loss of both effector and memory T-cell populations, downregulation of type 1 and upregulation of type 2 immune responses and decreased proliferation of effector T cells in the presence of tumors. Curcumin, in turn, prevented this loss of T cells, expanded central memory T cell (T(CM))/effector memory T cell (T(EM)) populations, reversed the type 2 immune bias and attenuated the tumor-induced inhibition of T-cell proliferation in tumor-bearing hosts. Further investigation revealed that tumor burden upregulated Treg cell populations and stimulated the production of the immunosuppressive cytokines transforming growth factor (TGF)-beta and IL-10 in these cells. Curcumin, however, inhibited the suppressive activity of Treg cells by downregulating the production of TGF-beta and IL-10 in these cells. More importantly, curcumin treatment enhanced the ability of effector T cells to kill cancer cells. Overall, our observations suggest that the unique properties of curcumin may be exploited for successful attenuation of tumor-induced suppression of cell-mediated immune responses.

Although safe in most cases, ancient treatments are ignored because neither their active components nor their molecular targets are well defined. This is not the case, however, with curcumin, a yellow-pigment substance and component of turmeric (Curcuma longa), which was identified more than a century ago. Recently, extensive research has addressed the chemotherapeutic potential of this relatively nontoxic-plant-derived polyphenol. Because most cancers are caused by deregulation of as many as 500 different genes, agents that target multiple gene products are needed for prevention and treatment of cancer. In this regard, curcumin has been reported to have immense potentiality for being used in cancer chemotherapy because of its control over the machineries of cell survival, proliferation, invasion, and angiogenesis. The mechanisms implicated are diverse and appear to involve a combination of cell signaling pathways at multiple levels. This review seeks to summarize the unique multifocal signal modulatory properties of the "ancient weapon," curcumin, which may be exploited for successful clinical cancer prevention.

Background: Many tumors are associated with decreased cellular immunity and elevated levels of prostaglandin E2 (PGE2), a known inhibitor of CD4+ T cell activation and inducer of type-2 cytokine bias. However, the role of this immunomodulator in the survival of T helper cells remained unclear. Since CD4+ T cells play critical roles in cell-mediated immunity, detail knowledge of the effect tumor-derived PGE2 might have on CD4+ T cell survival and the underlying mechanism may, therefore, help to overcome the overall immune deviation in cancer., Methodology/principal Findings: By culturing purified human peripheral CD4+ T cells or Jurkat cells with spent media of theaflavin- or celecoxib-pre-treated MCF-7 cells, we show that tumor-shed PGE2 severely impairs interleukin 2 receptor gammac (IL2Rgammac)-mediated survival signaling in CD4+ T cells. Indeed, tumor-shed PGE2 down-regulates IL2Rgammac expression, reduces phosphorylation as well as activation of Janus kinase 3 (Jak-3)/signal transducer and activator of transcription 5 (Stat-5) and decreases Bcl-2/Bax ratio thereby leading to activation of intrinsic apoptotic pathway. Constitutively active Stat-5A (Stat-5A1 6) over-expression efficiently elevates Bcl-2 levels in CD4+ T cells and protects them from tumor-induced death while dominant-negative Stat-5A over-expression fails to do so, indicating the importance of Stat-5A-signaling in CD4+ T cell survival. Further support towards the involvement of PGE2 comes from the results that (a) purified synthetic PGE2 induces CD4+ T cell apoptosis, and (b) when knocked out by small interfering RNA, cyclooxygenase-2 (Cox-2)-defective tumor cells fail to initiate death. Interestingly, the entire phenomena could be reverted back by theaflavins that restore cytokine-dependent IL2Rgammac/Jak-3/Stat-5A signaling in CD4+ T cells thereby protecting them from tumor-shed PGE2-induced apoptosis., Conclusions/significance: These data strongly suggest that tumor-shed PGE2 is an important factor leading to CD4+ T cell apoptosis during cancer and raise the possibility that theaflavins may have the potential as an effective immunorestorer in cancer-bearer.

Patients with advanced cancer exhibit multifaceted defects in their immune capacity, which are likely to contribute to an increased susceptibility to infections and disease progression. We demonstrated earlier that curcumin inhibits tumor growth and prevents immune cell death in tumor-bearing hosts. Here we report that tumor-induced immunodepletion involves apoptosis of thymic CD4+/CD8+ single/double positive cells as well as loss of circulating CD4+/CD8+ T cells. Administration of curcumin to tumor-bearing animals resulted in restoration of progenitor, effecter, and circulating T cells. In fact, tumor burden decreased the expression level of the pro-proliferative protein Bcl-2 while increasing the pro-apoptotic protein Bax in T cells. Curcumin down-regulated the Bax level while augmenting Bcl-2 expression in these cells, thereby protecting the immunocytes from tumor-induced apoptosis. A search for the upstream mechanism revealed down-regulation of the common cytokine receptor gamma chain (gammac) expression in T cells by tumor-secreted prostaglandin E2. As a result, Jak-3 and Stat-5a phosphorylation and to a lesser extent Stat-5b phosphorylation were also decreased in T cells. These entire phenomena could be reverted back by curcumin, indicating that this phytochemical restored the cytokine-dependent Jak-3/Stat-5a signaling pathway in T cells of tumor bearers. Overexpressed Stat-5a/constitutively active Stat-5a1*6 but not Stat-5b could efficiently elevate Bcl-2 levels and protect T cells from tumor-induced death, whereas C-terminal truncated Stat-5a713 overexpression failed to do so, indicating the importance of Stat-5a signaling in T cell survival. Thus, these results raise the possibility of inclusion of curcumin in successful therapeutic regimens against cancer.

Purpose: Previously, we have synthesized and characterized a novel Cu(II) complex, copper N-(2-hydroxy acetophenone) glycinate (CuNG). Herein, we have determined the efficacy of CuNG in overcoming multidrug-resistant cancer using drug-resistant murine and human cancer cell lines., Experimental Design: Action of CuNG following single i.m. administration (5 mg/kg body weight) was tested in vivo on doxorubicin-resistant Ehrlich ascites carcinoma (EAC/Dox)-bearing mice and doxorubicin-resistant sarcoma 180-bearing mice. Tumor size, ascitic load, and survival rates were monitored at regular intervals. Apoptosis of cancer cells was determined by cell cycle analysis, confocal microscopy, Annexin V binding, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay ex vivo. IFN-gamma and tumor necrosis factor-alpha were assayed in the culture supernatants of in vivo and in vitro CuNG-treated splenic mononuclear cells from EAC/Dox-bearing mice and their apoptogenic effect was determined. Source of IFN-gamma and changes in number of T regulatory marker-bearing cells in the tumor site following CuNG treatment were investigated by flow cytometry. Supernatants of in vitro CuNG-treated cultures of peripheral blood mononuclear cells from different drug-insensitive cancer patients were tested for presence of the apoptogenic cytokine IFN-gamma and its involvement in induction of apoptosis of doxorubicin-resistant CEM/ADR5000 cells., Results: CuNG treatment could resolve drug-resistant cancers through induction of apoptogenic cytokines, such as IFN-gamma and/or tumor necrosis factor-alpha, from splenic mononuclear cells or patient peripheral blood mononuclear cells and reduce the number of T regulatory marker-bearing cells while increase infiltration of IFN-gamma-producing T cells in the ascetic tumor site., Conclusion: Our results show the potential usefulness of CuNG in immunotherapy of drug-resistant cancers irrespective of multidrug resistance phenotype.

The preparation of a polyazamacrocyclic-nitrotriazole conjugate for radiolabeling with the therapeutic radioisotope viz. (177)Lu is described. The nitroimidazole used for the present study is [N-2'(carboxyethyl)-2-(3'-nitro-1'-triazolyl)acetamide], the carboxylic acid derivative of sanazole, which possesses an optimal combination of desired properties such as, selective toxicity for hypoxic cells, lowered lipophilicity resulting in lowered neurotoxicity. The bifunctional chelating agent is a DOTA derivative viz. 1,4,7,10-tetraaza-1-(4'-aminobenzylacetamido)-cyclododecane-4,7,10- triacetic acid (p-amino-DOTA-anilide). (177)Lu was produced in adequate specific activity (110TBq/g) and high radionuclidic purity (approximately 100%) by irradiating enriched (60.6% (176)Lu) Lu(2)O(3) target and used for radiolabeling of the sanazole-BFCA conjugate. approximately 98% Complexation yield was achieved under optimized conditions. The complex has been characterized by paper chromatography and HPLC studies. Bioevaluation studies in Swiss mice bearing fibrosarcoma tumors revealed moderate tumor uptake (0.88%/g at 1h post-injection) with favorable tumor to blood (4.00 at 1h post-injection) and tumor to muscle (4.63 at 1h post-injection) ratios.

177Lu of specific activity approximately 100-110 TBq/g and radionuclidic purity of approximately 100% was obtained by irradiation of enriched Lu2O3 (60.6% 176Lu) target for 7 days at a thermal neutron flux of 3 x 10(13)n/cm2/sec. The 177Lu labeling of a macrocyclic bifunctional chelating agent viz. 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) has been extensively studied. Lanreotide, [beta-naphthyl-Ala-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2] a disulfide-linked cyclic octapeptide and a somatostatin analog, reported to bind with a wide variety of tumors expressing somatostatin receptors, was conjugated with DOTA. The peptide-BFCA conjugate was characterized with the help of high-resolution two-dimensional proton NMR spectroscopy. The 177Lu labeling of the DOTA-lanreotide conjugate has been standardized to give a radiolabeling yield of 85%. The tracer showed specific binding with A-431 human epidermoid carcinoma and IMR-32 human brain neuroblastoma cells., (Copyright 2004 Elsevier Inc.)

Background Cancer development is aggravated by a rare population of cells, termed cancer stem cells (CSCs), that uniquely initiates and sustains the disease. Although CSCs can orchestrate the immune systems in favour of tumor, the detailed mechanisms underlying their immunomodulatory effects remain elusive. Recent reports indicate the contribution of exosomes, secreted from various cells, as mediators of cell-to-cell communication and also as a mediator of immune modulation in the tumor microenvironment. Methods Breast CSCs (bCSCs) were purified from breast cancer cell lines and human breast tumor tissues following which CSC-derived exosomes (CDEs) were isolated. Peripheral blood mononuclear cells were isolated from the blood of healthy donors and breast cancer patients, co-cultured with CDEs, and T regulatory (Treg) cell generation was evaluated. Results We found that bCSCs are able to generate CD4+CD25+FOXP3+ Treg cells having suppressive activity. Our search for the underlying mechanism revealed for the first time that bCSC-secreted exosomes contain FOXP3 protein that uniquely initiates acquisition of Treg characteristics in the infiltrating T lymphocytes. Exosomes from FOXP3-ablated bCSCs failed to augment Treg cell generation indicating the requirement of bCSC-gifted FOXP3 in Treg generation. Interestingly, perturbation of transcription or translation in T naïve cells significantly decreased CDE-augmented FOXP3 level signifying that CDE-FOXP3 utilizes the transcription and translational machineries of T naïve cells to induce Treg cell generation. In fact, exosome-shuttled FOXP3 binds to the CNS2 region of the Foxp3 promoter in T lymphocytes, thus resulting in a sustained expression of FOXP3 and further leading to induction of other genes of Foxp3 interactome, thereby phenotypically converting the T cells to Treg cells. Conclusions Collectively our data demonstrates that bCSC-shed exosomal FOXP3 plays an important role in procreation of Treg cells within the tumor microenvironment thus leading to tumor-induced immune suppression. Breaching the deadly-liaison between them might be a promising strategy for breast cancer therapy. Legal entity responsible for the study Prof. Tanya Das, Professor, Division of Molecular Medicine, Bose Institute. Funding Department of Science and Technology, Govt. of Inda Council of Scientific & Industrial Research (CSIR), Govt. of India. Disclosure All authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]