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Addition of the valproic acid (histone deacetylases inhibitor) to a culture of an endophytic fungus Diaporthe sp. harbored from Datura inoxia significantly altered its secondary metabolic profile and resulted in the isolation of three novel compounds, identified as xylarolide A (1), diportharine A (2) and xylarolide B (3) along with one known compound xylarolide (4). The structures of all the compounds (1-4) were determined by detailed analysis of 1D and 2D NMR spectroscopic data. The relative configurations of compounds 1-3 were determined with the help of NOESY data and comparison of optical rotations with similar compounds with established stereochemistry. All the isolated compounds were screened for antibacterial, antioxidant and cytotoxic activities. Xylarolide A (1) and xylarolide (4) displayed significant growth inhibition of MIAPaCa-2 with an IC 50 of 20 and 32 µM respectively and against PC-3 with an IC 50 of 14 and 18 µM respectively. Moreover, compound 1 displayed significant DPPH scavenging activity with EC 50 of 10.3 µM using ascorbic acid as a positive control., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

A series of chalcone linked-1,2,3-triazoles was synthesized via cellulose supported copper nanoparticle catalyzed click reaction in water. The structures of all the compounds were analyzed by IR, NMR and Mass spectral techniques. All the synthesized products were subjected to 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cytotoxicity assay against a panel of four human cancer cell lines (MCF-7, MIA-Pa-Ca-2, A549, HepG2) to check their anticancer potential. Compound 6h was found to be most active against all the tested cancer cell lines with IC 50 values in the range of 4-11 μM and showed better or comparable activity to the reference drug against all the tested cell lines. Cell cycle analysis revealed that compound 6h induces apoptosis and G2/S arrest in MIA-Pa-Ca-2 cells. Compound 6h triggers mitochondrial potential loss in pancreatic cancer MIA-Pa-Ca-2 cells. Further, Compound 6h also triggers caspase-3 and PARP-1 cleavage, which increases in dose dependent manner., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Nanotechnology-based drug products are emerging as promising agents to enhance the safety and efficacy of established chemotherapeutic molecules. Carbon nanotubes (CNTs), especially multiwalled CNTs (MWCNTs), have been explored for this potential owing to their safety and other desired attributes. Docetaxel (DTX) is an indispensable anticancer agent, which has wide applicability in variety of cancers. However, the potential of DTX is still not completely harvested due to problems like poor aqueous solubility, low tissue permeability, poor bioavailability, high first pass metabolism, and dose-related toxicity. Hence, it was proposed to attach DTX to MWCNTs and coadminister it along with piperine with an aim to enhance the tissue permeation, anticancer activity, and bioavailability. The Fourier transform infrared, UV, and NMR spectroscopic data confirmed successful conjugation of DTX to MWCNTs and adsorption of piperine onto MWCNTs. The codelivery MWCNT-based system offered drug release moderation and better cancer cell toxicity than that of plain DTX as well as DTX-CNT conjugate. The pharmacokinetic profile of DTX was exceptionally improved by the conjugation, in general, and coadministration with piperine, in specific vis-à-vis plain drug. Hence, the dual approach of MWCNTs conjugation and piperine coadministration can serve as a beneficial option for enhancement of the performance of DTX in cancer chemotherapy.

Docetaxel is one of the promising drugs and employed for the management of variety of cancers. However, challenges like poor-bioavailability, low tissue-permeability, compromised aqueous solubility and dose-dependent side-effects limit its clinical applications. Whereas, PLGA-based polymeric micelles possess the ability to enhance the tissue permeability of drugs and increase their biocompatibility. Henceforth, it was aimed to fabricate the dextran-PLGA-based polymeric-micelles loaded with docetaxel to explore the potential benefits in drug delivery. Dextran was chemically linked to PLGA and the linkage was confirmed by FT-IR, UV and NMR-spectroscopy. Critical-micelle-concentration of amphiphilic polymer was determined and drug was encapsulated by diffusion technique and erythrocyte compatibility. The system was evaluated for drug release profile and in vitro cytotoxicity studies. The pharmacokinetic profile was studied in rats. The micelles obtained were of 96.5±2.5nm and offered drug encapsulation of order of 54.85±1.21%.The cytotoxicity of drug against MCF-7 and MDA-MB-231 cell lines was enhanced by approx. 100%. The pharmacokinetic profile was substantially modified and about 16-folds enhancement in bioavailability was observed vis-à-vis plain drug. The approach was not only able to control the drug release, but also offered promise to enhance the pharmacokinetic and pharmacodynamic potential of docetaxel and similar anticancer agents., (Copyright © 2016 Elsevier B.V. All rights reserved.)

We have developed a dual function carrier using bishexadecyltrimethyl ammonium palladium tetrachloride, which has anticancer as well as antibacterial activity, using a ligand insertion method with a simple and easy work procedure. The complex is prepared by a simple and cost effective method using hexadecyltrimethyl ammonium chloride and palladium chloride under controlled stoichiometry. Herein, we report the aggregation (self assembly) of the metallosurfactant having palladium as a counter ion, in aqueous medium along with its binding affinity with bovine serum albumin. The palladium surfactant has exhibited excellent antimicrobial efficacy against fungus and bacteria (both Gram-positive and Gram-negative bacteria). Cytotoxicity of palladium surfactant against cancerous (Human leukemia HL-60, pancreatic MIA-Pa-Ca-2 and prostate cancer PC-3) and healthy cells (fR2 human breast epithelial cells) was also evaluated using MTT assay. The present dual functional moiety shows a low IC50 value and has potential to be used as an anticancer agent. Our dual function carrier which itself possesses antimicrobial and anticancer activity represents a simple and effective system and can also be utilized as a drug carrier in the future.

In an attempt to arrive at more potent cytotoxic agent than the bioactive natural product betulinic acid, influence of small structural modifications of its 1, 2, 3 triazole derivatives tethered at C-28 and both C3, C-28 using click chemistry approach has been studied. The chemically characterized triazoles have been screened for in vitro cytotoxicity against four human cancer cell lines HL-60, MiaPaCa-2, PC-3 and A549 which has allowed to identify triazole derivative 28{1N (4-fluoro phenyl)-1H-1, 2, 3-triazol-4-yl} methyloxy betulinic ester having better potency profile than the parent compound with IC50 values in the range of 5-7 μM. It caused disruption of mitochondrial membrane potential, rendered Bcl-2 cleavage, Bax translocation and decrease Bcl-2/Bax ratio. These events are accompanied by activation of caspases -9, -3, which cleave the PARP-1. It also induces caspase-8, which is involved in extrinsic apoptotic pathway. Therefore, it induces apoptosis through both intrinsic and extrinsic pathways in human leukemia HL-60 cells., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Docetaxel has always attracted the researchers owing to its promises and challenges. Despite marked efficacy, concerns like poor aqueous solubility, lower bioavailability, poor tissue penetration and dose related side-effects offer further scope of research on docetaxel. The present study aims to explore the potential of C60-fullerenes in the delivery of docetaxel to cancerous cells. C60-fullerenes were carboxylated, acylated and conjugated with the drug. The chemical processes were monitored by UV, FT-IR and NMR spectroscopy. The conjugate was further characterized for drug loading, micromeritics, drug release, morphology and evaluated for in-vitro cytotoxicity, haemolysis and in-vivo pharmacokinetic profile. The developed nanoconstruct was able to enhance the bioavailability of docetaxel by 4.2 times and decrease the drug clearance by 50%. The developed system was able to control the drug release and was found to be compatible with erythrocytes. The cytotoxic potential on studied MCF-7 and MDA-MB231 cell lines was also enhanced by many folds, indicating marked promise in efficacy enhancement and dose reduction. The present findings are encouraging and offer a technique to enhance the delivery and efficacy potential of anticancer agents, especially belonging to BCS class IV., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Colchicine (1), a nature-derived microtubule polymerization inhibitor, develops multi-drug resistance in tumor cells due to its P-gp substrate and induction activity, which in turn leads to its rapid efflux from tumor cells. This auto-induction of the efflux of colchicine remains a major challenge to medicinal chemists. Based on structure-based molecular modeling, a series of new colchicine derivatives were designed and synthesized with a potential for reduced P-gp induction liability. Screening of the prepared derivatives for P-gp induction activity revealed that a number of derivatives possess remarkably lower P-gp-induction activity (>90% intracellular accumulation of rhodamine 123 in LS-180 cells) compared to the parent natural product colchicine (62% Rh123 accumulation in LS-180 cells). The reduced P-gp-induction activity of new derivatives may be due to their reduced ability to interact and change the conformation of P-gp. The synthesized derivatives were then screened for antiproliferative activity against two colon cancer cell lines including HCT-116 and Colo-205. The derivative 4o showed potent cytotoxicity in HCT-116 cells with IC50 of 0.04 μM with significantly reduced P-gp induction liability. Compound 4o also inhibited microtubule assembly and induced expression of pro-apoptotic protein p21. In an Ehrlich solid tumor mice model, compound 4o showed 38% TGI with no mortality at 2 mg kg(-1) dose (oral). Compound 4o, with potent in vitro and in vivo anticancer activity, significantly reduced P-gp induction activity and its excellent physicochemical and pharmacokinetic properties open up new opportunities for the colchicine scaffold.

3-((Quinolin-4-yl)methylamino)-N-(4-(trifluoromethoxy)phenyl)thiophene-2-carboxamide (OSI-930, 1) is a potent inhibitor of c-kit and VEGFR2, currently under phase I clinical trials in patients with advanced solid tumors. In order to understand the structure-activity relationship, a series of 3-arylamino N-aryl thiophene 2-carboxamides were synthesized by modifications at both quinoline and amide domains of the OSI-930 scaffold. All the synthesized compounds were screened for in vitro cytotoxicity in a panel of cancer cell lines and for VEGFR1 and VEGFR2 inhibition. Thiophene 2-carboxamides substituted with benzo[d][1,3]dioxol-5-yl and 2,3-dihydrobenzo[b][1,4]dioxin-6-yl groups 1l and 1m displayed inhibition of VEGFR1 with IC50 values of 2.5 and 1.9 μM, respectively. Compounds 1l and 1m also inhibited the VEGF-induced HUVEC cell migration, indicating its anti-angiogenic activity. OSI-930 along with compounds 1l and 1m showed inhibition of P-gp efflux pumps (MDR1, ABCB1) with EC50 values in the range of 35-74 μM. The combination of these compounds with doxorubicin led to significant enhancement of the anticancer activity of doxorubicin in human colorectal carcinoma LS180 cells, which was evident from the improved IC50 of doxorubicin, the increased activity of caspase-3 and the significant reduction in colony formation ability of LS180 cells after treatment with doxorubicin. Compound 1l showed a 13.8-fold improvement in the IC50 of doxorubicin in LS180 cells. The ability of these compounds to display dual inhibition of VEGFR and P-gp efflux pumps demonstrates the promise of this scaffold for its development as multi-drug resistance-reversal agents.

Tubulin binding compounds represent one of the most attractive targets for anticancer drug development. They broadly fall into two categories viz., tubulin polymerization inhibitors, which block microtubule growth and destabilize microtubules like vinca alkaloids and cryptophycins, and the others, which polymerize microtubules into hyperstable forms represented by family of taxanes. In this context, we aimed at design and synthesis of cryptophycins based macrocyclic depsipeptides, which are synthetically more accessible, however have the basic information to target tubulins and establish structure activity relationship (SAR). Thus, a new class of cryptophycins based marocyclic depsipeptides with a truncated epoxide chain were synthesized as potential tubulin inhibitors. The resultant lead analogues 15a and 16a exhibited good anti-cancer activity, induced apoptosis, caused block/delay in cell cycle as well as significantly reduced the expression of α- and β-tubulins. Molecular modelling studies show that 15a and 16a bind in the same domain as that of cryptophycins., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Leukemia is one of the deadliest types of cancer. Lack of effective treatment strategies has resulted in an extensive quest for new therapeutic molecules against it. This study explores the molecular mechanism of anticancer activity of P16, a semisynthetic analog of parthenin, against the human acute lymphoblastic leukemia MOLT-4 cells. P16 displayed antiproliferative activity in different cancer cell lines; however, MOLT-4 cells showed highest sensitivity for P16 with IC50 value of 0.6μM. Further studies revealed that P16 induced cell death by apoptosis. It caused mitochondrial stress, which was mediated by the translocation of Bax from cytosol to mitochondria and release of cytochrome c into the cytosol and consequent activation of caspase-9. However, P16 was also able to activate caspase-8, thus involving both extrinsic and intrinsic pathways of apoptosis. Further, activation of caspase-3 led to cleavage of its target proteins PARP-1 and ICAD, which resulted in apoptotic DNA damage. P16 induced apoptosis was accompanied by the down-regulation of important leukemic cell survival proteins like pAKT (S473), pAKT (T308), pP70S6K, pCRAF, and pERK1/2. However, inhibition of caspases by Z-VAD-FMK reversed the down-regulatory effect of P16 on pAKT (S473) and pP70S6K, as evident by the cell viability assay and flow cytometric analysis but this inhibition did not completely reverse the antiproliferative effect of P16, thereby indicating the role of additional factors apart from caspases in P16 induced apoptosis in MOLT-4 cells. Owing to its antiproliferative potential against leukemia cells, P16 can further be explored as an effective therapeutics against leukemia., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

A target synthesis of a library of symmetric aromatic diselenides was attempted with the aim of generating anticancer lead compounds. Out of thirteen screened molecules (1-13) against a panel of human cancer cell lines, compound 8 exhibited highest cell growth inhibition in Human leukemia HL-60 cells with IC50 value of 8 μM. Compound 8 had a good pro-apoptotic potential as evidenced from several apoptotic protocols like DNA cell cycle analysis and monitoring of apoptotic bodies formation using phase contrast and nuclear microscopy with Hoechst 33,258. Also, 8 significantly inhibits S phase of the cell cycle and eventually trigger apoptosis in HL-60 cells through mitochondrial dependent pathway substantiated by the loss of mitochondrial potential. A theoretical investigation of DNA binding ability of 8 showed that it selectively bind to minor groove of DNA, where it is stabilized by hydrogen bonding and hydrophobic interactions., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

A microwave assisted strategy for synthesis of series of 1H-pyrazolo[4,3-d]pyrimidin-7(6H)-ones has been developed and their biological evaluation as anticancer agents is described. The synthetic protocol involves simple procedure by oxidative coupling of 4-amino-1-methyl-3-propyl-1H-pyrazole-5-carboxamide with different aldehydes in presence of K2S2O8 offering 5-substituted-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one compounds in excellent yields. The in vitro anticancer activity screening against human cancer cell lines HeLa, CAKI-I, PC-3, MiaPaca-2, A549 gave good results. The in detailed mechanistic correlation studies of compound 3m revealed that the compound shows anticancer activity through apoptosis mechanism and also inhibits mTOR with nonomolar potency. The design was based on docking with mTOR protein. The concentration dependent cell cycle analysis, western blotting experiment and nuclear cell morphology studies have been described., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Mallotus B (2d) is a prenylated dimeric phloroglucinol compound isolated from Mallotus philippensis. There have been no reports on the synthesis or biological activity of this compound. In the present paper, a semisynthetic preparation of mallotus B is reported via base-mediated intramolecular rearrangement of rottlerin (1), which is one of the major constituents of M. philippensis. The homodimer "rottlerone" was also formed as one of the products of this base-mediated intramolecular reaction. Rottlerin (1), along with rottlerone (2c) and mallotus B (2d), was evaluated for cytotoxicity against a panel of cancer cell lines including HEPG2, Colo205, MIAPaCa-2, PC-3, and HL-60 cells. Mallotus B (2d) displayed cytotoxicity for MIAPaCa-2 and HL-60 cells with IC₅₀ values of 9 and 16 μM, respectively. Microscopic studies in HL-60 cells indicated that mallotus B (2d) induces cell cycle arrest at the G1 phase and causes defective cell division. It also induces apoptosis, as evidenced by distinct changes in cell morphology.

This study describes the mechanism of trolox and tiron induced potentiation of cytotoxicity caused by Ery5, an analog of magnolol, in human myeloid leukemia HL-60 cells. Ery5 induced cytotoxicity in HL-60 cells by involving activation of bax and cleavage of caspase 3, which contributed towards activation of both apoptotic and autophagic pathways. Trolox and tiron, even at non-toxic concentrations, contributed to the cytotoxicity of Ery5 by activation of autophagic proteins like ATG7, ATG12 and LC3-II. Z-VAD-fmk mediated reduction in the cytotoxicity and expression of autophagic proteins, further suggested that autophagy induced by Ery5 is largely dependent upon caspases. Interestingly, Ery5 induced autophagy was accompanied by the downregulation of PI3K/AKT pathway whereas, trolox and tiron strongly enhanced this effect. In addition to that treatment of cells with Ery5, trolox and tiron individually, displayed a marked upregulation of Bax. The involvement of Bax in trolox and tiron induced enhancement of the cytotoxicity of Ery5 was confirmed, when siRNA induced silencing of Bax led to increased viability of the cells and exerted a strong inhibitory effect on LC3-II accumulation and p62 degradation in case of cells treated by the combination of Ery5 with trolox or tiron. Additionally, an important role of PARP in Ery5 mediated cell death has been suggested by PARP silencing experiments, however, potentiation of autophagic cytotoxicity by trolox and tiron did not seem to be dependent on PARP-1. Therefore, Bax seems to play a vital role in trolox and tiron mediated potentiation of autophagic cell death by Ery5 in HL-60 cells.

A pentacyclic triterpenediol (TPD) from Boswellia serrata has significant cytotoxic and apoptotic potential in a large number of human cancer cell lines. To enhance its anticancer potential, it was successfully formulated into solid lipid nanoparticles (SLNs) by the microemulsion method with 75% drug entrapment efficiency. SEM and TEM studies indicated that TPD-SLNs were regular, solid, and spherical particles in the range of 100-200 nm, and the system indicated that they were more or less stable upon storing up to six months. TPD loaded SLNs showed significantly higher cytotoxic/antitumor potential than the parent drug. TPD-SLNs have 40-60% higher cytotoxic and apoptotic potential than the parent drug in terms of IC(50), extent of apoptosis, DNA damage, and expression of pro-apoptotic proteins like TNF-R1, cytochrome-c, and PARP cleavage in HL-60 cells. Moreover, blank SLNs did not have any cytotoxic effect on the cancer as well as in normal mouse peritoneal macrophages. The in vivo antitumor potential of TPD-SLNs was significantly higher than that of TPD alone in Sarcoma-180 solid tumor bearing mice. Therefore, SLNs of TPD successfully increased the apoptotic and anticancer potential of TPD at comparable doses (both in vitro and in vivo). This work provides new insight into improvising the therapeutic efficacy of TPD by adopting novel delivery strategies such as solid lipid nanoparticles.

Thiazolo[5,4-d]pyrimidines are important class of heterocyclic compounds possessing diverse range of biological activities. Herein, we report an efficient synthesis of thiazolo[5,4-d]pyrimidines using recyclable KF/alumina catalyst. The reaction of 4,6-dichloro-5-aminopyrimidine with isothiocyanates in presence of 20 mol% KF/alumina produced thiazolo[5,4-d]pyrimidines in excellent yields without any chromatographic purifications. The method is operationally simple, fast and the catalyst can be reused without any significant loss of activity. These compounds were tested for antiproliferative activity in a panel of 8 cancer cell lines, including lung (NCI-H322 and A549), epidermal (A431), glioblastoma (T98G), pancreatic (MIAPaCa-2), prostate (PC-3), human leukemia (HL-60) and breast (T47D) cells. The N,N'-diethylamino-substituted analog, 2-(4-chlorophenylamino)-7-diethylamino-thiazolo[5,4-d]pyrimidine 4k showed antiproliferative activity in lung (NCI-H322 and A549), epidermal (A431) and glioblastoma (T98G) cancer cell lines with IC50 values of 7.1, 1.4, 3.1 and 3.4 μM, respectively. The morpholine substituted analog 4a displayed activity in HL-60 cells with IC50 value of 8 μM. The compound 4k showed induction of apoptosis in A549 cells at 10 μM, as indicated by the increase in the sub-G1 population. The nuclear morphology of A549 cells after treatment with 4k was also investigated. Similarly, the morpholine substituted analog 4a induced apoptosis in HL-60 cells at 20 μM. The effect of compound 4a on mitochondrial potential loss in HL-60 cells was also studied. Further, western blotting of 4a and 4k showed cleavage of PARP-1 and procaspase-3 inhibition which confirms their apoptosis-inducing activity., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

The present study describes anticancer effect of gallic acid based indanone derivative (1). Indanone 1 exhibited in vivo anticancer activity against Erhlich ascites carcinoma in Swiss albino mice by inhibiting tumor growth by 54.3% at 50 mg/kg b.wt. It showed antitubulin effect by inhibiting tubulin polymerase enzyme. In cell cycle analysis, it inhibited G2/M phase and induced apoptosis. It significantly suppressed VEGF-R1, VEGF-R2 and HIF-α in human breast cancer MCF-7 cells, thus exhibiting antiangiogenic activity. In acute oral toxicity, indanone 1 was well tolerated and was found to be non-toxic up to 1000 mg/kg b.wt. in Swiss albino mice. Pharmacokinetic studies in rabbits revealed rate of absorption, half life, volume of distribution with high plasma and blood clearance after i.v. administration. Indanone 1, is a safe and moderately active anticancer agent., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Intervention of apoptosis is a promising strategy for discovery of novel anti-cancer therapeutics. In this study, we examined the ability of a novel cyano derivative of 11-keto-β-boswellic acid, that is, butyl 2-cyano-3,11-dioxours-1,12-dien-24-oate (BCDD) to induce apoptosis in cancer cells. BCDD inhibited cell proliferation with 48 h IC(50) of 0.67 µM in HL-60, 1 µM in Molt4, and 1.5 µM in THP1 cells. The mechanism of cell death was investigated in HL-60 cells where it caused apoptosis by acting against several potential apoptosis suppressive targets. It inhibited phosphatidylinositol-3-kinase (PI3K)/AKT activity, NF-κB, Hsp-90, and survivin which may enhance the sensitivity of cells to apoptosis. Also, BCDD decreased the activity of Bid and Bax in cytosol, caused ΔΨ(mt) loss, releasing pro-apoptotic cytochrome c, SMAC/DIABLO leading to caspase-9-mediated down stream activation of caspase-3, ICAD, and PARP1 cleavage. Translocation of apoptotis-inducing factor (AIF) from mitochondria to the nucleus indicated some caspases-independent apoptosis. Though it upregulated DR-5 and caspase-8, the caspase inhibitor yet had no effect on apoptosis as against 75% inhibition by caspase-9 inhibitor. Attempts were made to examine any acclaimed role of AIF in the activation of caspase-8 using siRNA where it had no effect on caspase-8 activity while the Bax-siRNA inhibited caspase-3 activation suggesting predominance of intrinsic signaling. Our studies thus demonstrated that BCDD exerts multi-focal action in cancer cells while it required 10-fold higher the concentration to produce cytotoxicity in normal human PBMC and gingival cell line, and therefore, may find usefulness in the management of human leukemia., (Copyright © 2011 Wiley Periodicals, Inc.)

This study describes the anti-cancer activity of P19, an analog of parthenin. P19 induced apoptosis in HL-60 cells and inhibited cell proliferation with 48h IC50 of 3.5μM. At 10mg/kg dose, it doubled the median survival time of L1210 leukemic mice and at 25mg/kg it inhibited Ehrlich ascites tumor growth by 60%. Investigation of the mechanism of P19 induced apoptosis in HL-60 cells revealed that N-acetyl-l-cysteine (NAC) and s-methylisothiourea (sMIT) could reverse several molecular events that lead to cell death by inhibiting nitric oxide (NO) formation. It selectively produced massive NO in cells while quenching the basal ROS levels with concurrent elevation of GSH. P19 disrupted mitochondrial integrity leading to cytochrome c release and caspase-9 activation. P19 also caused caspase-8 activation by selectively elevating the expression of DR4 and DR5. All these events lead to the activation of caspase-3 leading to PARP-1 cleavage and DNA fragmentation. However, knocking down of AIF by siRNA also suppressed the apoptosis substantially thus indicating caspase independent apoptosis, too. Further, contrary to enhanced iNOS expression, its transcription factor, NF-κB (p65) was cleaved with a simultaneous increase in cytosolic IκB-alpha. In addition, P19 potently inhibited pro-survival proteins pSTAT3 and survivin. The multi-modal pro-apoptotic activity of P19 raises its potential usefulness as a promising anti-cancer therapeutic., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Antioxidants have been used as adjuvant with anticancer therapy to synergize the potential of the anti-neoplastic therapeutics. Based on the fact, we have studied the effect of three natural antioxidants curcumin, silymarin and acteoside on AP9-cd (standardized lignan composition from Cedrus deodara) induced cytotoxicity in human leukemia HL-60 cells. The antioxidant potential of individual test compounds was first evaluated with ferric reducing antioxidant power (FRAP) test, which revealed that all four molecules behave as antioxidants. The apoptotic potential of AP9-cd was significantly enhanced in HL-60 cells in the presence of curcumin, silymarin and acteoside. It was confirmed by using various models like MTT assay, DNA fragmentation, nuclei condensation, sub-Go DNA population, Annexin-V-FITC binding, ROS depletion and immunoblotting in HL-60 cells. AP9-cd and individual antioxidants alone at low doses (10μg and 10μM, respectively) have meager or no cytotoxicity in HL-60 cells, whereas in mutual combinations, there were 2-3 times enhancement in Annexin-V-FITC and sub-Go DNA population. Moreover, prominent DNA ladders were observed at low doses of AP9-cd in combinations with various antioxidants. The Hoechst staining of the nucleus also revealed the same results for the HL-60 cells treated with AP9-cd and different antioxidants. The molecular diagnostics revealed that the combinations induced a strong antioxidant effect which was correlated with the downregulation of NF-κB expression in the nucleus. Out of the three antioxidants, curcumin was found to be more potent than acteoside and silymarin in terms of enhancing the apoptotic potential of AP9-cd. These results propose an important role of natural antioxidant as adjuvant to enhance the anticancer potential of AP9-cd and more likely other anti-neoplastic therapeutics., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Inula racemosa Hook.f. commonly known as Pushkarmula (Compositae) has been used as a traditional drug in India, China and Europe. In the present study, 95% ethanolic extract of roots and its fractions (n-hexane, chloroform, n-butanol and aqueous) were evaluated for in vitro cytotoxicity against cancer cell lines of colon, ovary, prostate, lung, CNS and leukemia. The n-hexane fraction containing alantolactone and isoalantolactone as its major constituents was further studied for its mode of action in HL-60 cells. The lowest IC(50) value of n-hexane fraction was 10.25 microg/ml for Colo-205, a colon cancer cell line whereas, 17.86 microg/ml was the highest IC(50) value observed against CNS cancer cell line SF-295. Further studies on HL-60 cells treated with n-hexane fraction at 10, 25 and 50 microg/ml for 6h, revealed that it induces apoptosis through intrinsic as well as extrinsic pathways by generating reactive oxygen species (ROS) intermediates. Mitochondrial dysfunction prompted the release of cytochrome c, translocation of pro-apoptotic protein (Bax), activation of caspase cascade, resulting in the cleavage of some specific substrates for caspase-3 such as poly (ADP-ribose) polymerase (PARP), which eventually leads to apoptosis. The results of present study strongly support further research and development of bioactive constituents from Inula racemosa as potential anticancer agent with possible therapeutic implication., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Induction of apoptosis in cancer cells has become the major focus of anti-cancer therapeutics development. WithaferinA, a major chemical constituent of Withania somnifera, reportedly shows cytotoxicity in a variety of tumor cell lines while its molecular mechanisms of action are not fully understood. We observed that withaferinA primarily induces oxidative stress in human leukemia HL-60 cells and in several other cancer cell lines. The withanolide induced early ROS generation and mitochondrial membrane potential (Deltapsi(mt)) loss, which preceded release of cytochrome c, translocation of Bax to mitochondria and apoptosis inducing factor to cell nuclei. These events paralleled activation of caspases -9, -3 and PARP cleavage. WA also activated extrinsic pathway significantly as evidenced by time dependent increase in caspase-8 activity vis-à-vis TNFR-1 over expression. WA mediated decreased expression of Bid may be an important event for cross talk between intrinsic and extrinsic signaling. Furthermore, withaferinA inhibited DNA binding of NF-kappaB and caused nuclear cleavage of p65/Rel by activated caspase-3. N-acetyl-cysteine rescued all these events suggesting thereby a pro-oxidant effect of withaferinA. The results of our studies demonstrate that withaferinA induced early ROS generation and mitochondrial dysfunction in cancer cells trigger events responsible for mitochondrial -dependent and -independent apoptosis pathways.

A triterpenediol (TPD) comprising of isomeric mixture of 3alpha, 24-dihydroxyurs-12-ene and 3alpha, 24-dihydroxyolean-12-ene from Boswellia serrata induces apoptosis in cancer cells. An attempt was made in this study to investigate the mechanism of cell death by TPD in human leukemia HL-60 cells. It inhibited cell proliferation with IC50 approximately 12 microg/ml and produced apoptosis as measured by various biological end points e.g. increased sub-G0 DNA fraction, DNA ladder formation, enhanced AnnexinV-FITC binding of the cells. Further, initial events involved massive reactive oxygen species (ROS) and nitric oxide (NO) formation, which were significantly inhibited by their respective inhibitors. Persistent high levels of NO and ROS caused Bcl-2 cleavage and translocation of Bax to mitochondria, which lead to loss of mitochondrial membrane potential (Deltapsim) and release of cytochrome c, AIF, Smac/DIABLO to the cytosol. These events were associated with decreased expression of survivin and ICAD with attendant activation of caspases leading to PARP cleavage. Furthermore, TPD up regulated the expression of cell death receptors DR4 and TNF-R1 level, leading to caspase-8 activation. These studies thus demonstrate that TPD produces oxidative stress in cancer cells that triggers self-demise by ROS and NO regulated activation of both the intrinsic and extrinsic signaling cascades.

We have developed a dual function carrier using bishexadecyltrimethyl ammonium palladium tetrachloride, which has anticancer as well as antibacterial activity, using a ligand insertion method with a simple and easy work procedure. The complex is prepared by a simple and cost effective method using hexadecyltrimethyl ammonium chloride and palladium chloride under controlled stoichiometry. Herein, we report the aggregation (self assembly) of the metallosurfactant having palladium as a counter ion, in aqueous medium along with its binding affinity with bovine serum albumin. The palladium surfactant has exhibited excellent antimicrobial efficacy against fungus and bacteria (both Gram-positive and Gram-negative bacteria). Cytotoxicity of palladium surfactant against cancerous (Human leukemia HL-60, pancreatic MIA-Pa-Ca-2 and prostate cancer PC-3) and healthy cells (fR2 human breast epithelial cells) was also evaluated using MTT assay. The present dual functional moiety shows a low IC50 value and has potential to be used as an anticancer agent. Our dual function carrier which itself possesses antimicrobial and anticancer activity represents a simple and effective system and can also be utilized as a drug carrier in the future. [ABSTRACT FROM AUTHOR]

AP9-cd, a novel lignan composition from Cedrus deodara has significant anticancer potential, and to further enhance its activity, it was lucratively encumbered into solid lipid nanoparticles (SLNs). These nanoparticles were formulated by micro-emulsion technique with 70% drug trap competence. AP9-cd-SLNs were regular, solid, globular particles in the range of 100–200 nm, which were confirmed by electron microscopic studies. Moreover, AP9-cd-SLNs were found to be stable for up to six months in terms of color, particle size, zeta potential, drug content and entrapment. AP9-cd-SLNs have 30–50% higher cytotoxic and apoptotic potential than the AP9-cd alone. The augmented anticancer potential of AP9-cd-SLNs was observed in cytotoxic IC 50 value, apoptosis signaling cascade and in Ehrlich ascites tumor (EAT) model. AP9-cd-SLNs induce apoptosis in Molt-4 cells via both intrinsic and extrinsic pathway. Moreover, the dummy nanoparticles (SLNs without AP9-cd) did not have any cytotoxic effect in cancer as well as in normal cells. Consequently, SLNs of AP9-cd significantly augment the apoptotic and antitumor potential of AP9-cd. The present study provides a podium for ornamental the remedial latent via novel delivery systems like solid lipid nanoparticles. [ABSTRACT FROM AUTHOR]

Background: While angiogenesis inhibitors represent a viable cancer therapy, there is preclinical and clinical data to suggest that many tumors develop resistance to such treatments. Moreover, previous studies have revealed a complex association between autophagy and angiogenesis, and their collective influence on tumorigenesis. Autophagy has been implicated in cytoprotection and tumor promotion, and as such may represent an alternative way of targeting apoptosis-resistant cancer cells. This study explored the anti-cancer agent and boswellic acid analog BA145 as an inducer of autophagy and angiogenesis-mediated cytoprotection of tumor cells. Methods: Flow cytometry, western blotting, and confocal microscopy were used to investigate the role of BA145 mediated autophagy. ELISA, microvessel sprouting, capillary structure formation, aortic ring and wound healing assays were performed to determine the relationship between BA145 triggered autophagy and angiogenesis. Flow cytometery, western blotting, and microscopy were employed to examine the mechanism of BA145 induced cell death and apoptosis. Live imaging and tumor volume analysis were carried out to evaluate the effect of BA145 triggered autophagy on mouse tumor xenografts. Results: BA145 induced autophagy in PC-3 cancer cells and HUVECs significantly impeded its negative regulation on cell proliferation, migration, invasion and tube formation. These effects of BA145 induced autophagy were observed under both normoxic and hypoxic conditions. However, inhibition of autophagy using either pharmacological inhibitors or RNA interference enhanced the BA145 mediated death of these cells. Similar observations were noticed with sunitinib, the anti-angiogenic properties of which were significantly enhanced during combination treatments with autophagy inhibitors. In mouse tumor xenografts, co-treatment with chloroquinone and BA145 led to a considerable reduction in tumor burden and angiogenesis compared to BA145 alone. Conclusion: These studies reveal the essential role of BA145 triggered autophagy in the regulation of angiogenesis and cytoprotection. It also suggests that the combination of the autophagy inhibitors with chemotherapy or anti-angiogenic agents may be an effective therapeutic approach against cancer. [ABSTRACT FROM AUTHOR]

BACKGROUND Apple pomace is generated in huge quantities in juice-processing industries the world over and continuous efforts are being made for its inclusive utilization. In this study, apple seeds separated from industrial pomace were used for extraction of oil. The fatty acid composition, physicochemical and antioxidant as well as in vitro anticancer properties of extracted oil were studied to assess its suitability in food and therapeutic applications. RESULTS The fatty acid composition of seed oil revealed the dominance of oleic (46.50%) and linoleic acid (43.81%). It had high iodine (121.8 g I 100 g−1) and saponification value (184.91 mg KOH g−1 oil). The acid value, refractive index and relative density were 4.28 mg KOH g−1, 1.47 and 0.97 mg mL−1, respectively. The antioxidant potential ( IC50) of apple seed oil was 40.06 µg mL−1. Cytotoxicity of apple seed oil against CHOK1, SiHa and A549 cancer cell lines ranged between 0.5 ± 0.06% and 88.6 ± 0.3%. CONCLUSION The physicochemical properties of apple seed oil were comparable with edible food oil, indicating its better stability and broad application in the food and pharmaceutical industries. Apple seed oil could be a good source of natural antioxidants. Also, the in vitro cytotoxic activity against specific cell lines exhibited its potential as an anticancer agent. © 2013 Society of Chemical Industry [ABSTRACT FROM AUTHOR]

Objective To evaluate Carissa spinarum stem isolate for its anti-cancer therapeutic potential. Methods The n-butanol fraction of aqueous extract from Carissa spinarum stem was assessed for its cytotoxic and pro-apoptotic activity. Key findings We report for the first time the anti-cancer potential of C. spinarum stem aqueous extract (CSE) and its n-butanol fraction (CSF). Both inhibited cell proliferation of various human cancer cell lines in which leukaemia HL-60 cells treated with CSF showed maximum growth inhibition having an inhibitory concentration (IC50) value of 34.58 ± 0.91 µg/ml. In addition, CSF induced concentration-dependent apoptosis in HL-60 cells as measured by various end-points (e.g. Annexin V binding, DNA laddering, apoptotic body formation and an increase in hypodiploid subG0 DNA content). Moreover, persistent levels of reactive oxygen species caused translocation of Bax to mitochondria and Bcl-2 degradation, which led to loss of mitochondrial membrane potential and release of cytochrome c to the cytosol. These events were associated with significant activation of caspase-3, caspase-6 and caspase-9 leading to poly (ADP-ribose) polymerase cleavage. Conclusion All the above parameters revealed that CSF induced apoptosis through the mitochondrial dependent pathway in HL-60 cells. [ABSTRACT FROM AUTHOR]

Bioassay-guided fractionation of the fruits of Piper longum afforded two new minor amides, piperlongimin A (2) [2E-N-isobutyl-hexadecenamide] and piperlongimin B (4) [2E-octadecenoylpiperidine] together with five known compounds with moderate cytotoxic activity. The structures were elucidated on the basis of spectroscopic evidences. All these compounds inhibited cell proliferation of human leukemia, HL-60 cell lines, and displayed major apoptosis-inducing effects. [ABSTRACT FROM AUTHOR]

Tamoxifen is a nonsteroidal estrogen-receptor modulator widely used in the treatment of breast cancer. Apoptosis has been reported to be a major mechanism for its antitumor effect. In the current studies, an endeavor was made to investigate the efficacy of vesicularly encapsulated tamoxifen on human breast cancer MCF-7 cells. Phospholipid-based vesicular systems viz. conventional liposomes and elastic-membrane liposomes were employed to encapsulate the drug. The MTT colorimetric assay was used to determine the efficacy of the tested formulations. The results demonstrated composition-dependent strong inhibition in the viability of MCF-7 cells with encapsulated tamoxifen vis-à-vis free drug. The encouraging findings from the current work construe immense potential of the lipid-based vesicular systems in the treatment of breast cancer. [ABSTRACT FROM AUTHOR]

Abstract: Deregulated apoptosis and suppressed tumour reactive immunity render tumour cells to grow amok in the host body. Traditionally used botanicals may offer potential anticancer chemo-immunotherapeutic leads. We report in this study a chemically standardised herbal formulation (WSF) of Withania somnifera possessing anticancer and Th1 immune up-regulatory activities. WSF produced cytotoxicity in a panel of human cancer cell lines in vitro. The molecular mechanism of cell cytotoxicity, IC50 48h ∼20μg/ml, was investigated in HL-60, where it induced apoptosis by activating both intrinsic and extrinsic signalling pathways. It induced early generation of reactive nitrogen and oxygen species (RNOS), thus producing oxidative stress mediated mitochondrial membrane potential (MMP) loss leading to the release of cytochrome c, the translocation of Bax to mitochondria and apoptosis-inducing factor to the nuclei. These events paralleled the activation of caspase-9, -3 and PARP cleavage. WSF also activated caspase-8 through enhanced expression of TNF-R1 and DR-4, suggesting also the involvement of extrinsic pathway of apoptosis. WSF at 150mg/kg, i.p., inhibited >50% tumour growth in the mouse tumour models. In tumour-bearing mice, WSF inhibited the expression of pStat-3, with a selective stimulation of Th1 immunity as evidenced by enhanced secretion of IFN-γ and IL-2. In parallel, it enhanced the proliferation of CD4+/CD8+ and NK cells along with an increased expression of CD40/CD40L/CD80. In addition, WSF also enhanced T cell activation in camptothecin treated tumour-bearing mice. WSF being safe when given orally up to 1500mg/kg to rats for 6 months may be found useful in the management of malignancy by targeting at multiple pathways. [Copyright &y& Elsevier]

Abstract: Polyalthia longifolia is a lofty evergreen tree found in India and Sri Lanka. We are reporting first time the anticancer potential of P. longifolia leaves extract (A001) and its chloroform fraction (F002). Both inhibited cell proliferation of various human cancer cell lines in which colon cancer cells SW-620 showed maximum inhibition with IC50 value 6.1μg/ml. Furthermore, F002 induce apoptosis in human leukemia HL-60 cells as measured by several biological end points. F002 induce apoptotic bodies formation, DNA ladder, enhanced annexin-V-FITC binding of the cells, increased sub-G0 DNA fraction, loss of mitochondrial membrane potential (ΔΨ mt), release of cytochrome c, activation of caspase-9, caspase-3, and cleavage of poly ADP ribose polymerase (PARP) in HL-60 cells. All the above parameters revealed that F002-induced apoptosis through the mitochondrial-dependent pathway in HL-60 cells. [Copyright &y& Elsevier]

Isoform-selective inhibition of PI3K-α has been identified as one of the important strategy to discover effective and safer anticancer agents. Herein, we report discovery of ‘quinazoline’ as a new chemotype for isoform-selective PI3K-α inhibitors. The indolyl substituted quinazoline 9u displayed selective inhibition of PI3K-α with IC 50 value of 0.201 μM with >49.7 over PI3K-β, and δ-isoforms. Quinazoline 9u also inhibited PI3K-γ with IC 50 value of 0.750 μM (3.7 fold selective for α- versus γ-isoform). The isoform-selective inhibition was also demonstrated at protein-expression level by western-blot analysis in MCF-7 and PC-3 cells. The isoform-selective inhibitor 9u also showed inhibition of phospho-Akt levels in these cells. Quinazoline 9u showed in-vitro cytotoxicity in MCF-7 cells with GI 50 of 7 μM, which was highly selective for cancer cells, as it was non-toxic to normal cells fR2, HEK293 and hGF (GI 50 > 50 μM). Compound 9u at 25 mg/kg dose showed 62 and 37% TGI in Ehrlich Ascites Carcinoma and Ehrlich Solid Tumor mice models. In nutshell, our efforts to identify potent and efficacious PI3K inhibitors resulted in the discovery of a new class of isoform-selective PI3K-α inhibitors possessing promising in-vivo anticancer activity. [ABSTRACT FROM AUTHOR]

Rohitukine is a chromone alkaloid isolated from an Indian medicinal plant Dysoxylum binectariferum . This natural product has led to the discovery of two clinical candidates (flavopiridol and P276-00) for the treatment of cancer. Herein, for the first time we report an efficient protocol for isolation and purification of this precious natural product in a bulk-quantity from leaves (a renewable source) of D. binectariferum (>98% purity) without use of chromatography or any acid–base treatment. Despite of the fact that this scaffold has reached up to clinical stage, particularly for leukemia; however the antileukemic activity of a parent natural product has never been investigated. Furthermore, rohitukine has never been studied for cyclin-dependent kinase (Cdk) inhibition, kinase profiling and for its experimental physicochemical properties. Thus, herein, we report in vitro cytotoxicity of rohitukine in a panel of 20 cancer cell lines (including leukemia, pancreatic, prostate, breast and CNS) and 2 normal cell lines; kinase profiling, Cdk2/9 inhibition, and physicochemical properties (solubility and stability in biological medias, p K a , Log P , Log D ). In cytotoxicity screening, rohitukine displayed promising activity in HL-60 and Molt-4 (leukemia) cell lines with GI 50 of 10 and 12 μM, respectively. It showed inhibition of Cdk2/A and Cdk9/T1 with IC 50 values of 7.3 and 0.3 μM, respectively. The key interactions of rohitukine with Cdk9 was also studied by molecular modeling. Rohitukine was found to be highly water soluble ( S water = 10.3 mg/mL) and its Log P value was −0.55. The ionization constant of rohitukine was found to be 5.83. Rohitukine was stable in various biological media’s including rat plasma. The data presented herein will help in designing better anticancer agents in future. [ABSTRACT FROM AUTHOR]

Tumor angiogenesis is a validated target for therapeutic intervention, but agents that are more disease selective are needed. Here, we report the isolation of secalonic acid-D (SAD), a mycotoxin from a novel source that exhibits potent antiangiogenic antitumor activity. SAD inhibited multiple HIF1α/VEGF-arbitrated angiogenesis dynamics as scored in human umbilical vascular endothelial cells and human MCF-7 breast tumor xenografts. Similarly, SAD suppressed VEGF-induced microvessel sprouting from rat aortic ring and blood vessel formation in the Matrigel plug assay in C57/BL6J mice. Under normoxic or hypoxic conditions, SAD inhibited cell survival through the Akt/mTOR/p70S6K pathway, with attendant effects on key proangiogenesis factors, including HIF1α, VEGFR, and MMP-2/MMP-9. These effects were reversed by cotreatment with the Akt inhibitors perifosine and GSK69069 or by the addition of neutralizing VEGF antibodies. The apoptotic properties of SAD were determined to be both extrinsic and intrinsic in nature, whereas the cell-cycle inhibitory effects were mediated by altering the level of key G1-S transition-phase proteins. In experimental mouse models of breast cancer, SAD dosing produced no apparent toxicities (either orally or intraperitoneal) at levels that yielded antitumor effects. Taken together, our findings offered a preclinical validation and mechanistic definition of the antiangiogenic activity of a novel mycotoxin, with potential application as a cancer-selective therapeutic agent. [ABSTRACT FROM AUTHOR]

Highlights: [•] We have isolated four metabolites from stem bark of Erythrina suberosa. [•] α-Hydroxyerysotrine, 4-Methoxy licoflavanone, Alpinumisoflavone and Wighteone. [•] They inhibit NF-κB and STAT signaling pathway. [•] They induce apoptosis through extrinsic and intrinsic pathways. [ABSTRACT FROM AUTHOR]

The in vitro anticancer screening of new compounds (III) (20 examples) against human cancer cell lines (HeLa, CAKI-I, PC-3, MiaPaca-2, A549) gives good results. [ABSTRACT FROM AUTHOR]