Apoptosis and cell cycle arrest of leukemic cells by a robust and stable L-asparaginase from Pseudomonas sp. PCH199.

Biomolecules obtained from microorganisms living in extreme environments possess properties that have pharmacokinetic advantages. Enzyme assay revealed recombinant L-ASNase, an extremozyme from Pseudomonas sp. PCH199 is to be highly stable with 90 % activity (200 h) at 37 °C. The stability of the enzyme in human serum (50 % activity maintained in 63 h) reveals high therapeutic potential with less dosage. The enzyme exhibited cytotoxicity to K562 blood cancer cell lines with IC50 of 0.37 U/mL without affecting the IEC-6 normal epithelial cell line. Due to the depletion of L-asparagine, K562 cells experience nutritional stress that results in the abruption of metabolic processes and eventually leads to apoptosis. Comparative studies on MCF-7 cells also revealed the same fate. Due to nutritional stress induced by L-ASNase treatment, mitochondrial membrane potential was lost, and reactive oxygen species were increased to 48 % (K562) and 21 % (MCF-7) as indicated by flow cytometric analysis. DAPI staining with prominent nuclear morphological changes visualized under the fluorescent microscope confirmed apoptosis in both cancer cells. Treatment increases pro-apoptotic Bax protein, and eventually, the cell cycle is arrested at the G2/M phase in both cell lines. Therefore, the current study paves the way for PCH199 L-ASNase to be considered a potential chemotherapeutic agent for treating acute lymphoblastic leukemia.

Amorphous solid dispersion augments the bioavailability of phloretin and its therapeutic efficacy via targeting mTOR/SREBP-1c axis in NAFLD mice.

The escalating incidences of non-alcoholic fatty liver disease (NAFLD) and associated metabolic disorders are global health concerns. Phloretin (Ph) is a natural phenolic compound, that exhibits a wide array of pharmacological actions including its efficacy towards NAFLD. However, poor solubility and bioavailability of phloretin limits its clinical translation. Here, to address this concern we developed an amorphous solid dispersion of phloretin (Ph-SD) using Soluplus® as a polymer matrix. We further performed solid-state characterization through SEM, P-XRD, FT-IR, and TGA/DSC analysis. Phloretin content, encapsulation efficiency, and dissolution profile of the developed formulation were evaluated through reverse phase HPLC. Finally, the oral bioavailability of Ph-SD and its potential application in the treatment of experimental NAFLD mice was investigated. Results demonstrated that the developed formulation (Ph-PD) augments the dissolution profile and oral bioavailability of the native phloretin (Ph). In NAFLD mice, histopathological studies revealed the preventive effect of Ph-SD on degenerative changes, lipid accumulation, and inflammation in the liver. Ph-SD also improved the serum lipid profile, ALT, and AST levels and lowered the interleukin-6 and tumor necrosis factor-α levels in the liver. Further, Ph-SD reduced fibrotic changes in the liver tissues and attenuates NAFLD progression by blocking the mTOR/SREBP-1c pathway. In a nutshell, the results of our study strongly suggest that Ph-SD has the potential to be a therapeutic candidate in the treatment of NAFLD and can be carried forward for further clinical studies.

Phloretin suppresses intestinal inflammation and maintained epithelial tight junction integrity by modulating cytokines secretion in in vitro model of gut inflammation.

Ulcerative colitis is a type of inflammatory bowel disease which in long run can lead to colorectal cancer (CRC). Chronic inflammation can be a key factor for the occurrence of CRC thus mitigating an inflammation can be a preventive strategy for the occurrence of CRC. In this study we have explored the anti-inflammatory potential of phloretin, in in vitro gut inflammation model, developed by co-culture of Caco2 (intestinal epithelial) cells and RAW264.7 macrophages (immune cells). Phloretin is a dihydrochalcone present in apple, pear and strawberries. An anti-inflammatory effect of phloretin in reducing LPS induced inflammation and maintenance of transepithelial electric resistance (TEER) in Caco2 cells was examined. Paracellular permeability assay was performed using Lucifer yellow dye to evaluate the effect of phloretin in inhibiting gut leakiness caused by inflammatory mediators secreted by activated macrophages. Phloretin attenuated LPS induced nitric oxide levels, oxidative stress, depolarization of mitochondrial membrane potential in Caco2 cells as evidenced by reduction in reactive oxygen species (ROS), and enhancement of MMP, and decrease in inflammatory cytokines IL8, TNFα, IL1ß and IL6. It exhibited anti-inflammatory activity by inhibiting the expression of NFκB, iNOS and Cox2. Phloretin maintained the epithelial integrity by regulating the expression of tight junction proteins ZO1, occludin, Claudin1 and JAM. Phloretin reduced LPS induced levels of Cox2 along with the reduction in Src expression which further regulated an expression of tight junction protein occludin. Phloretin in combination to sodium pyruvate exhibited potential anti-inflammatory activity via targeting NFkB signaling. Our findings paved a way to position phloretin as nutraceutical in preventing the occurrence of colitis and culmination of disease into colitis associated colorectal cancer.

Phloretin induces G2/M arrest and apoptosis by suppressing the ß-catenin signaling pathway in colorectal carcinoma cells.

Colorectal carcinoma (CRC) is the third most prevalent cancer, causing a significant mortality worldwide. Present available therapies are surgery, chemotherapy including radiotherapy, and these are known to be associated with heavy side effects. Therefore, nutritional intervention in the form of natural polyphenols has been well recognised to prevent CRC. Phloretin, a known dihydrochalcone is present in apple, pear and strawberry. This has been proven to induce apoptosis in cancer cells and also exhibited anti-inflammatory activity, thus can be explored as a potential anticancer nutraceutical agent. This study demonstrated phloretin's significant in vitro anticancer activity against CRC. Phloretin suppressed cell proliferation, colony forming ability and cellular migration in human colorectal cancer HCT-116 and SW-480 cells. Results also revealed that phloretin generated reactive oxygen species (ROS) which provoked depolarization of mitochondrial membrane potential (MMP) and further contributed to cytotoxicity in colon cancer cells. Phloretin also modulated the cell cycle regulators including cyclins and cyclin-dependent kinases (CDKs) and halted cell cycle at G2/M phase. Moreover, it also induced apoptosis by regulating the expression of Bax and BCl-2. The Wnt/ß-catenin signaling is inactivated by phloretin by targeting the downstream oncogenes namely CyclinD1, c-Myc and Survivin which are involved in the proliferation and apoptosis of colon cancer cells. In our study we showed that lithium chloride (LiCl) induced the expression of ß-catenin and its target genes and the co-treatment of phloretin circumvent its effect and downregulated the Wnt/ß-catenin signaling. In conclusion, our results strongly suggested that phloretin can be utilized as a nutraceutical anticancer agent for combating CRC.

Biochemical characterization of extremozyme L-asparaginase from Pseudomonas sp. PCH199 for therapeutics.

L-asparaginase (L-ASNase) from microbial sources is a commercially vital enzyme to treat acute lymphoblastic leukemia. However, the side effects associated with the commercial formulations of L-ASNases intrigued to explore for efficient and desired pharmacological enzymatic features. Here, we report the biochemical and cytotoxic evaluation of periplasmic L-ASNase of Pseudomonas sp. PCH199 isolated from the soil of Betula utilis, the Himalayan birch. L-ASNase production from wild-type PCH199 was enhanced by 2.2-fold using the Response Surface Methodology (RSM). Increased production of periplasmic L-ASNase was obtained using an optimized osmotic shock method followed by its purification. The purified L-ASNase was a monomer of 37.0 kDa with optimum activity at pH 8.5 and 60 ℃. It also showed thermostability retaining 100.0% (200 min) and 90.0% (70 min) of the activity at 37 and 50 ℃, respectively. The Km and Vmax values of the purified enzyme were 0.164 ± 0.009 mM and 54.78 ± 0.4 U/mg, respectively. L-ASNase was cytotoxic to the K562 blood cancer cell line (IC50 value 0.309 U/mL) within 24 h resulting in apoptotic nuclear morphological changes as examined by DAPI staining. Therefore, the dynamic functionality in a wide range of pH and temperature and stability of PCH199 L-ASNase at 37 ℃ with cytotoxic potential proves to be pharmaceutically important for therapeutic application.

MAPKAPK2-centric transcriptome profiling reveals its major role in governing molecular crosstalk of IGFBP2, MUC4, and PRKAR2B during HNSCC pathogenesis.

Transcriptome analysis of head and neck squamous cell carcinoma (HNSCC) has been pivotal to comprehending the convoluted biology of HNSCC tumors. MAPKAPK2 or MK2 is a critical modulator of the mRNA turnover of crucial genes involved in HNSCC progression. However, MK2-centric transcriptome profiles of tumors are not well known. This study delves into HNSCC progression with MK2 at the nexus to delineate the biological relevance and intricate crosstalk of MK2 in the tumor milieu. We performed next-generation sequencing-based transcriptome profiling of HNSCC cells and xenograft tumors to ascertain mRNA expression profiles in MK2-wild type and MK2-knockdown conditions. The findings were validated using gene expression assays, immunohistochemistry, and transcript turnover studies. Here, we identified a pool of crucial MK2-regulated candidate genes by annotation and differential gene expression analyses. Regulatory network and pathway enrichment revealed their significance and involvement in the HNSCC pathogenesis. Additionally, 3'-UTR-based filtering recognized important MK2-regulated downstream target genes and validated them by nCounter gene expression assays. Finally, immunohistochemistry and transcript stability studies revealed the putative role of MK2 in regulating the transcript turnover of IGFBP2, MUC4, and PRKAR2B in HNSCC. Conclusively, MK2-regulated candidate genes were identified in this study, and their plausible involvement in HNSCC pathogenesis was elucidated. These genes possess investigative values as targets for diagnosis and therapeutic interventions for HNSCC.

Novel 3-Methyleneisoindolinones Diversified via Intramolecular Heck Cyclization Induce Oxidative Stress, Decrease Mitochondrial Membrane Potential, Disrupt Cell Cycle, and Induce Apoptosis in Head and Neck Squamous Cell Carcinoma Cells.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most prevalent cancer in the world and the most prevalent cancer of developing countries. Increased disease burden and a smaller number of approved targeted therapies are a growing concern worldwide. Isoindolinone motifs have been a central part of many pharmacological compounds, and their derivatives possess substantial anticancer potential. However, their anticancer potential against HNSCC has not been well investigated. In the current study, a series of 3-methyleneisoindolinones have been designed and synthesized and their late-stage intramolecular Heck cyclization was achieved to evaluate their anticancer potential against HNSCC cells. Additionally, in silico ADME profiling of synthesized compounds revealed their drug-likeness properties as potential drug candidates. Among the synthesized compounds, 3-bromo-5-methylpyridin-2-yl-3-methyleneisoindolin-1-one, i.e., 3n, with a pyridyl unit exhibited the most significant cytotoxicity against HNSCC cells. The cytotoxic potential of synthesized compounds varied depending on the nature of substituents present and has been well established with structure-activity relationship studies. Further, flow cytometric analysis showed that 3f, 3h, and 3n triggered intracellular oxidative stress, disrupted mitochondrial membrane potential, and interrupted the cell cycle of HNSCC cells in the S-phase and sub-G1 phase. Further, 3f, 3h, and 3n also exhibited pro-apoptotic potential and induced cellular apoptosis in the HNSCC cells. Overall, the findings of this study attributed 3-methyleneisoindolinone chemistry and efficacy evaluation and corroborated their anticancer potential against HNSCC. It will pave the way to further design and optimize novel 3-methyleneisoindolinone as effective antitumor agents, which may provide effective treatment modalities against HNSCC.

DNA damage response proteins synergistically affect the cancer prognosis and resistance.

Amplification of oxidative stress can be utilized as a strategy to attenuate cancer progression by instigating apoptosis. However, the duration of positive response to such therapies is limited, as cancer cells eventually develop resistance. The underlying molecular mechanisms of cancer cells to escape apoptosis under oxidative stress is unknown. Employing big data, and its integration with transcriptome, proteome and network analysis in six cancer types revealed system-level interactions between DNA damage response (DDR) proteins, including; DNA damage repair, cell cycle checkpoints and anti-apoptotic proteins. Cancer system biology is used to elucidate mechanisms for cancer progression, but networks defining mechanisms causing resistance is less explored. Using system biology, we identified DDR hubs between G1-S and M phases that were associated with bad prognosis. The increased expression of DDR network was involved in resistance under high oxidative stress. We validated our findings by combining H2O2 induced oxidative stress and DDR inhibitors in human lung cancer cells to conclude the necessity of targeting a 'disease-causing network'. Collectively, our work provides insights toward designing strategies for network pharmacology to combat resistance in cancer research.

Steroidal saponins from Trillium govanianum as α-amylase, α-glucosidase, and dipeptidyl peptidase IV inhibitory agents.

OBJECTIVE: To provide the scientific basis for the utility of rhizome of Trillium govanianum as nutraceutical supplements in managing physiological glycemic levels. METHODS: The in vitro enzyme inhibitory activity of the extract, fractions, and the isolated steroidal saponins from the rhizome part of T. govanianum was carried out against α-amylase, α-glucosidase, and dipeptidyl peptidase IV. The molecular interactions, binding score, and pharmacokinetic parameters (absorption, distribution metabolism, and excretion) of steroidal saponins were analyzed by the Schrodinger molecular docking software. KEY FINDINGS: Current study explained that the extract, fractions, and isolated steroidal saponins from T. govanianum possess good α-amylase and α-glucosidase inhibitory activity while moderate dipeptidyl peptidase IV inhibitory activity. Moreover, in vitro results revealed that borassoside E (IC50 7.15 ± 1.78 µM), protodioscin (IC50 6.72 ± 0.04 µM), and diosgenin (IC50 12.75 ± 2.70 µM) are most effective in inhibiting the activity of α-amylase, α-glucosidase, and dipeptidyl peptidase IV, respectively. Current in silico and in vitro studies established an association between the steroidal saponins from T. govanianum and their molecular interactions with α-amylase, α-glucosidase, and dipeptidyl peptidase IV. CONCLUSION: The results of this investigation suggest that fractions and steroidal saponins from T. govanianum exhibit good antidiabetic activity which could be used as nutraceutical supplements for the management of systemic glucose level.

Narciclasine-4-O-ß-D-xylopyranoside, a new narciclasine glycoside from Zephyranthes minuta.

A new narciclasine glycoside, narciclasine-4-O-ß-D-xylopyranoside (1) was characterised along with four known alkaloids pancratistatin (2), 1-O-(3-hydroxybutyryl) pancratistatin (3), vittatine (4), 9-O-demethylgalanthine (5) from Zephyranthes minuta. Their structures were established on the basis of spectroscopic data analysis. The in vitro cytotoxic study of extract, fractions and isolated compounds against two human cancer cell lines (KB and SiHa) indicated the potential activity of extract and n-butanol fraction due to presence of active alkaloids pancratistatin, 1-O-(3-hydroxybutyryl) pancratistatin, lycorine and haemanthamine.

Pseudolycorine N-oxide, a new N-oxide from Narcissus tazetta.

A new N-oxide, Pseudolycorine N-oxide (1) was characterised along with eleven known alkaloids homolycorine (2), O-methylmaritidine (3), 8-O-demethylhomolycorine (4), homolycorine N-oxide (5), lycorine (6), narciclasine (7), pseudolycorine (8), ungeremine (9), 8-O-demethylmaritidine (10), zefbetaine (11) and lycorine N-oxide (12), from Narcissus tazetta. Their structures were established on the basis of spectroscopic data analysis. The extract, fractions and isolated compounds were screened for in vitro cytotoxicity against two human cancer cell lines, human cervical cancer (SiHa) and human epidermoid carcinoma (KB) cells. The study demonstrated the cytotoxic potential of extract and its chloroform and n-butanol fractions. Further, the results revealed the bioactive potential of narciclasine, pseudolycorine and homolycorine alkaloids. However, new N-oxide (1) was not active against these cell lines.

MAPKAPK2 plays a crucial role in the progression of head and neck squamous cell carcinoma by regulating transcript stability.

BACKGROUND: Head and neck squamous-cell carcinoma (HNSCC) ranks sixth among cancers worldwide. Though several molecular mechanisms of tumor initiation and progression of HNSCC are known, others remain unclear. Significance of p38/MAPKAPK2 (Mitogen-activated protein kinase-activated protein kinase-2) pathway in cell stress and inflammation is well established and its role in tumor development is being widely studied. METHODS: We have elucidated the role of MAPKAPK2 (MK2) in HNSCC pathogenesis using clinical tissue samples, MK2-knockdown (MK2KD) cells and heterotropic xenograft mice model. RESULTS: In patient-derived tissue samples, we observed that MK2 is reproducibly overexpressed. Increased stability of cyclin-dependent kinase inhibitor 1B (p27), mitogen-activated protein kinase phosphatase-1 (MKP-1) transcripts and decreased half-life of tumor necrosis factor-alpha (TNF-α) and vascular endothelial growth factor (VEGF) transcripts in MK2KD cells suggests that MK2 regulates their transcript stability. In vivo xenograft experiments established that knockdown of MK2 attenuates course of tumor progression in immunocompromised mice. CONCLUSION: Altogether, MK2 is responsible for regulating the transcript stability and is functionally important to modulate HNSCC pathogenesis.

MAPKAPK2: the master regulator of RNA-binding proteins modulates transcript stability and tumor progression.

The p38 mitogen-activated protein kinase (p38MAPK) pathway has been implicated in a variety of pathological conditions including inflammation and metastasis. Post-transcriptional regulation of genes harboring adenine/uridine-rich elements (AREs) in their 3'-untranslated region (3'-UTR) is controlled by MAPK-activated protein kinase 2 (MAPKAPK2 or MK2), a downstream substrate of the p38MAPK. In response to diverse extracellular stimuli, MK2 influences crucial signaling events, regulates inflammatory cytokines, transcript stability and critical cellular processes. Expression of genes involved in these vital cellular cascades is controlled by subtle interactions in underlying molecular networks and post-transcriptional gene regulation that determines transcript fate in association with RNA-binding proteins (RBPs). Several RBPs associate with the 3'-UTRs of the target transcripts and regulate their expression via modulation of transcript stability. Although MK2 regulates important cellular phenomenon, yet its biological significance in tumor progression has not been well elucidated till date. In this review, we have highlighted in detail the importance of MK2 as the master regulator of RBPs and its role in the regulation of transcript stability, tumor progression, as well as the possibility of use of MK2 as a therapeutic target in tumor management.

Allyl-isothiocyanate ameliorates the pre-neoplastic changes induced by the fern Dryopteris nigropalaceae on experimental feeding in Guinea pigs.

Enzootic bovine haematuria, caused by long-term ingestion of ferns, is a chronic disease of hill cattle characterized by neoplastic lesions in the urinary bladder. Objectives of this study were to investigate the toxicity potential of long-term feeding of the fern Dryopteris nigropalaceae and effect of allyl isothiocyanate (AITC) to ameliorate fern toxicity and the associated pathological changes. The LC-MS analysis of the fern showed presence of ptaquiloside (4.5 ±â€¯1.0 µg/g) and pterosin B (39 ±â€¯9.1 µg/g). Groups of animals were fed dried fern powder at the dose of 20% w/w in normal feed and treated with and without AITC at graded doses. Long term feeding of fern induced inflammatory and pre-neoplastic lesions in urinary bladder. The important lesions included cystitis, squamous metaplasia and high-grade dysplasia. Urothelium showed positive immunoreactions for nuclear expression of H-ras and p53. However, no mutation suggestive of neoplastic change was observed on partial mRNA sequences analyses of exon 2 of H-ras and 5 or 7&8 of p53 genes. Strikingly, AITC showed dose-dependent amelioration of pre-neoplastic changes in fern-fed animals. In conclusion, AITC is shown to limit pre-neoplastic changes caused by D. nigropalaceae feeding in guinea pigs.

Chemical Composition, Cytotoxic and Antibacterial Activities of Essential Oils of Cultivated Clones of Juniperus communis and Wild Juniperus Species.

Needles of seven cultivated clones (C1 - C7) of Juniperus communis at lower altitude and three wild Juniperus species (J. communis, J. recurva and J. indica) at higher altitudes were investigated comparatively for their essential oils (EOs) yields, chemical composition, cytotoxic and antibacterial activities. The EOs yields varied from 0.26 to 0.56% (v/w) among samples. Sixty-one volatile components were identified by gas chromatography-mass spectrometry (GC/MS) and quantified using gas chromatography GC (FID) representing 82.5 - 95.7% of the total oil. Monoterpene hydrocarbons (49.1 - 82.8%) dominated in all samples (α-pinene, limonene and sabinene as major components). Principal component analysis (PCA) of GC data revealed that wild and cultivated Juniperus species are highly distinct due to variation in chemical composition. J. communis (wild species) displayed cytotoxicity against SiHa (human cervical cancer), A549 (human lung carcinoma) and A431 (human skin carcinoma) cells (66.4 ± 2.2%, 74.4 ± 1.4% and 57.4 ± 4.0%), respectively, at 200 µg/ml. EOs exhibited better antibacterial activity against Gram-positive bacteria than against Gram-negative bacteria with the highest zone of inhibition against Staphylococcus aureus MTCC 96 (19.2 ± 0.7) by clone-7. As per the conclusion of the findings, EOs of clone-2, clone-5 and clone-7 can be suggested to the growers of lower altitude, as there is more possibility of uses of these EOs in food and medicinal preparations.

Anthocyanins enriched purple tea exhibits antioxidant, immunostimulatory and anticancer activities.

Purple coloured tea shoot clones have gained interest due to high content of anthocyanins in addition to catechins. Transcript expression of genes encoding anthocyanidin reductase (ANR), dihydroflavonol-4-reductase (DFR), anthocyanidin synthase (ANS), flavonol synthase (FLS) and leucoantho cyanidin reductase (LAR) enzymes in three new purple shoot tea clones compared with normal tea clone showed higher expression of CsDFR, CsANR, CsANS and lower expression of CsFLS and CsLAR in purple shoot clones compared to normal clone. Expression pattern supported high content of anthocyanins in purple tea. Four anthocyanins (AN1-4) were isolated and characterized by UPLC-ESI-QToF-MS/MS from IHBT 269 clone which recorded highest total anthocyanins content. Cyanidin-3-O-ß-d-(6-(E)-coumaroyl) glucopyranoside (AN2) showed highest in vitro antioxidant activity (IC50 DPPH = 25.27 ± 0.02 µg/mL and IC50 ABTS = 10.71 ± 0.01 µg/mL). Anticancer and immunostimulatory activities of cyanidin-3-glucoside (AN1), cyanidin-3-O-ß-d-(6-(E)-coumaroyl) glucopyranoside (AN2), delphinidin-3-O-ß-d-(6-(E)-coumaroyl) glucopyranoside (AN3), cyanidin-3-O-(2-O-ß-xylopyranosyl-6-O-acetyl)-ß-glucopyranoside (AN4) and crude anthocyanin extract (AN5) showed high therapeutic perspective. Anthocyanins AN1-4 and crude extract AN5 showed cytotoxicity on C-6 cancer cells and high relative fluorescence units (RFU) at 200 µg/mL suggesting promising apoptosis induction activity as well as influential immunostimulatory potential. Observations demonstrate potential of purple anthocyanins enriched tea clone for exploitation as a nutraceutical product.

In vivo diabetic wound healing potential of nanobiocomposites containing bamboo cellulose nanocrystals impregnated with silver nanoparticles.

In diabetes, hyperglycemic state immensely hinders the wound healing. Here, nanobiocomposites (NCs) developed by impregnation of in situ prepared silver nanoparticles in the matrix of bamboo cellulose nanocrystals were investigated for their ability to hasten the progress of healing events in streptozotocin induced diabetic mice model. Wounds treated with topically applied NCs (hydrogels) showed full recovery (98-100%) within 18days post wounding in contrast to the various control groups where incomplete healing (88-92%) was noticed. Biochemical estimations documented a marked decrease in the levels of pro-inflammatory cytokines IL-6 and TNF-α leading to decreased inflammation in NCs treated mice. Significantly increased expression of collagen and growth factors (FGF, PDGF, VEGF) upon NCs treatment resulted in improved re-epithelialization, vasculogenesis and collagen deposition as compared to control groups. Hence, developed nanobiocomposites showcased potential to serve as highly effective and biocompatible wound dressings for diabetic patients.

HIF-1 in cancer therapy: two decade long story of a transcription factor.

BACKGROUND: Oxygen (O2) homeostasis is an indispensable requirement of eukaryotes. O2 concentration in cellular milieu is defined as normoxia (∼21% O2), physoxia (∼1-13% O2) or hypoxia (∼0.1-1% O2). Hypoxia, a striking micro-environmental feature in tumorigenesis, is countered by tumor cells via induction of O2 governed transcription factor, hypoxia inducible factor-1 (HIF-1). Post discovery, HIF-1 has emerged as a promising anticancer therapeutic target during the last two decades. Recent reports have highlighted that enhanced levels of HIF-1 correlate with tumor metastasis leading to poor patient prognosis. MATERIAL AND METHODS: A systematic search in PubMed and SciFinder for the literature on HIF-1 biology and therapeutic importance in cancer was carried out. RESULTS: This review highlights the initial description as well as the recent insights into HIF-1 biology and regulation. We have focused on emerging data regarding varied classes of HIF-1 target genes affecting various levels of crosstalk among tumorigenic pathways. We have emphasized on the fact that HIF-1 acts as a networking hub coordinating activities of multiple signaling molecules influencing tumorigenesis. Emerging evidences indicate role of many HIF-induced proteomic and genomic alterations in malignant progression by mediating a myriad of genes stimulating angiogenesis, anaerobic metabolism and survival of cancer cells in O2-deficient microenvironment. CONCLUSIONS: Better understanding of the crucial role of HIF-1 in carcinogenesis could offer promising new avenues to researchers and aid in elucidating various open issues regarding the use of HIF-1 as an anticancer therapeutic target. In spite of large efforts in this field, many questions still remain unanswered. Hence, future investigations are necessary to devise, assess and refine methods for translating previous research efforts into novel clinical practices in cancer treatment.

Synergistic effect of curcumin and piperine in suppression of DENA-induced hepatocellular carcinoma in rats.

Curcumin has been reported to suppress different types of clinical and experimentally-induced tumors, but due to less absorption and quick metabolism it show poor bioavailability. The present study was envisaged to investigate the possible synergistic effect of combined treatment of curcumin with piperine in suppression of diethylnitrosamine (DENA)-induced hepatocellular carcinoma (HCC) in rats, owing to permeability enhancing effect of latter. HCC was induced by supplying DENA (0.01%) in drinking water for 10 weeks. The rats were treated with curcumin (100mg/kg; p.o.) per se and curcumin along with piperine (20mg/kg; p.o.) for 4 weeks post HCC induction. The combined treatment significantly attenuated the morphological, histopathological, biochemical, apoptotic and proliferative changes in the liver and serum in comparison to curcumin per se and vehicle control group. The results of present study concluded that curcumin in combination with piperine shows better suppression of DENA-induced HCC in contrast to curcumin per se.