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SUPPLEMENTARY FIGURE S1: General information and rationale of synthesis of hybrid molecules of Chalcone and Semicarbazone SUPPLEMENTARY FIGURE S2: Detailed qualitative analysis of compounds of Chalcone and Semicarbazone hybrid series Supplementary Figure S2a: NMR spectra and structure of compounds Supplementary Figure S2b: HPLC chromatogram of compounds Supplementary Figure S2c: Crystal structure of representative CS-24 SUPPLEMENTARY FIGURE S3: Dose dependent cytotoxic potential of CS-11 and parent compound 8e on different breast cell lines SUPPLEMENTARY FIGURE S4: Densitometric quantification and statistical analysis of western blots shown in Figure 2d SUPPLEMENTARY FIGURE S5: Effect of CS-11 on colon cancer cell growth inhibition and breast cancer cell migration Supplementary Figure S5a: IC50 and Dose dependent cytotoxic potential of CS-11 and parent compound 8e on SW620 colon cancer cell line Supplementary Figure S5b: Effect of CS-11 on breast cancer cell migration in in vitro scratch assay SUPPLEMENTARY FIGURE S6: Densitometric quantification and statistical analysis of western blots shown in Figure 5a (S6a) and 5c (S6b) SUPPLEMENTARY FIGURE S7: Densitometric quantification and statistical analysis of western blots shown in Figure 6a SUPPLEMENTARY TABLE S1: Crystal data and structure refinement details for representative compound CS-24 SUPPLEMENTARY TABLE S2: Cytotoxic potential of CS series on different cancer cell lines Supplementary Table S2a: Differential response of Chalcone Semicarbazone hybrids series on different cancer cells Supplementary Table S2b CS-11 induces breast cancer cell selective cytotoxic effects SUPPLEMENTARY METHODS Supplementary Method S1: Detailed procedure of compound synthesis Supplementary Method S2: X-Ray data collection and structure refinement details Supplementary Method S3: Methodology for pharmacokinetic studies

Ferroptosis, a genetically and biochemically distinct form of programmed cell death, is characterised by an iron-dependent accumulation of lipid peroxides. Therapy-resistant tumor cells display vulnerability toward ferroptosis. Endoplasmic Reticulum (ER) stress and Unfolded Protein Response (UPR) play a critical role in cancer cells to become therapy resistant. Tweaking the balance of UPR to make cancer cells susceptible to ferroptotic cell death could be an attractive therapeutic strategy. To decipher the emerging contribution of ER-stress in the ferroptotic process, we observe that ferroptosis inducer RSL3 promotes UPR (PERK, ATF6, and IRE1α), along with overexpression of cystine-glutamate transporter SLC7A11 (System Xc-). Exploring the role of a particular UPR arm in modulating SLC7A11 expression and subsequent ferroptosis, we notice that PERK is selectively critical in inducing ferroptosis in colorectal carcinoma. PERK inhibition reduces ATF4 expression and recruitment to the promoter ofSLC7A11and results in its downregulation. Loss of PERK function not only primes cancer cells for increased lipid peroxidation but also limits in vivo colorectal tumor growth, demonstrating active signs of ferroptotic cell deathin situ. Further, by performing TCGA data mining and using colorectal cancer patient samples, we demonstrate that the expression ofPERKandSLC7A11is positively correlated. Overall, our experimental data indicate that PERK is a negative regulator of ferroptosis and loss of PERK function sensitizes colorectal cancer cells to ferroptosis. Therefore, small molecule PERK inhibitors hold huge promise as novel therapeutics and their potential can be harnessed against the apoptosis-resistant condition.

Triple-negative breast cancers (TNBCs) are one of the most aggressive and complex forms of cancers in women. TNBCs are commonly known for their complex heterogeneity and poor prognosis. The present...

Triple-Negative Breast Cancer (TNBC) has a poor prognosis and adverse clinical outcomes among all breast cancer subtypes as there is no available targeted therapy. Overexpression of Enhancer of zeste homolog 2 (EZH2) has been shown to correlate with TNBC’s poor prognosis, but the contribution of EZH2 catalytic (H3K27me3) versus non-catalytic EZH2 (NC-EZH2) function in TNBC progression remains elusive. We reveal that selective hyper-activation of functional EZH2 (H3K27me3) over NC-EZH2 alters TNBC metastatic landscape and fosters its peritoneal metastasis, particularly splenic. Instead of H3K27me3-mediated repression of gene expression; here, it promotes KRT14 transcription by attenuating binding of repressor SP1 to its promoter. Further, KRT14 loss significantly reduces TNBC migration, invasion, and peritoneal metastasis. Consistently, human TNBC metastasis displays positive correlation between H3K27me3 and KRT14 levels. Finally, EZH2 knockdown or H3K27me3 inhibition by EPZ6438 reduces TNBC peritoneal metastasis. Altogether, our preclinical findings suggest a rationale for targeting TNBC with EZH2 inhibitors.

Chemokine receptor CXCR4 overexpression in solid tumors has been strongly associated with poor prognosis and adverse clinical outcome. However, blockade of CXCL12-CXCR4 signaling axis by inhibitors like Nox-A12, FDA approved CXCR4 inhibitor drug AMD3100 have shown limited clinical success in cancer treatment. Therefore, exclusive contribution of CXCR4-CXCL12 signaling in pro-tumorigenic function is questionable. In our pursuit to understand the impact of chemokine signaling in carcinogenesis, we reveal that instead of CXCR4-CXCL12 signaling, presence of CXCR4 intracellular protein augments paclitaxel resistance and pro-tumorigenic functions. In search of pro-apoptotic mechanisms for CXCR4 mediated drug resistance; we discover that DR5 is a new selective target of CXCR4 in breast and colon cancer. Further, we detect that CXCR4 directs the differential recruitment of transcription factors p53 and YY1 to the promoter of DR5 in course of its transcriptional repression. Remarkably, inhibiting CXCR4-ligand-mediated signals completely fails to block the above phenotype. Overexpression of different mutant versions of CXCR4 lacking signal transduction capabilities also result in marked downregulation of DR5 expression in colon cancer indeed confirms the reverse relationship between DR5 and intracellular CXCR4 protein expression. Irrespective of CXCR4 surface expression, by utilizing stable gain and loss of function approaches, we observe that intracellular CXCR4 protein selectively resists and sensitizes colon cancer cells against paclitaxel therapy in vitro and in vivo. Finally, performing TCGA data mining and using human breast cancer patient samples, we demonstrate that expression of CXCR4 and DR5 are inversely regulated. Together, our data suggest that targeting CXCR4 intracellular protein may be critical to dampen the pro-tumorigenic functions of CXCR4.

A simple and straightforward process for the synthesis of rapamycin peptide conjugates in a regio and chemoselective manner was developed. The methodology comprises the tagging of chemoselective functionalities to rapamycin and peptides which enables the conjugation of free peptides, without protecting the functionality of the side chain amino acids, in high yield and purity. From this methodology, we successfully conjugate free peptides containing up to 15 amino acids. Rapamycin is also conjugated to the peptides known for inhibiting the kinase activity of Akt protein. These conjugates act as dual target inhibitors and inhibit the kinase activity of both mTOR and Akt.

Plant extract possess various secondary metabolites which are antifungal in nature and can be used as a safer alternative to the synthetic fungicides. As we all know that the chemical fungicides are harmful not only for humans but also for animals, other vegetation and for complete ecosystem. To overcome this problem, we have to focused on another alternative which are biologically libel and nonhazardous also. In the present study, herbal formulation was prepared in various combination ratios with

Alternaria solani, a plant pathogenic fungus causes significant economical losses of potato crop. The disease is controlled primarily through some traditional methods and most commonly via the application of chemical fungicides. Fungicides treatment is not protected as chemicals pollute environment, effect health vulnerability in humans and when these harmful chemicals enter into the food chain become hazardous to all living entities. Recent efforts have focused on developing environmentally safe, long-lasting, and effective biocontrol methods for the management of plant diseases. Present research focus on screening of crude and partially purified leaf extract of Thevetia peruviana for the presence of antifungal efficacy against Alternarai solani. It was observed that 100% alcoholic crude and alcoholic fraction of partially purified extract showed maximum inhibitory activity which is due to the presence of different secondary metabolites, revealed by phytochemical screening. Active column fraction (possess best antifungal activity against Alternaria solani) was subjected to Gas Chromatography-Mass Spectrometry (GS-MS) analysis. On the basis of peaks matching of GC-MS chromatogram with available data base showed the presence of benzoic acid and oxo-benzoate in active fraction of Thevetia peruviana leaf extract which is already known chemical among the phytochemicals described for antimicrobial activity. Further research on development of herbal formulation from the same would be very helpful environment friendly approach to manage concern crop disease.

Ferroptosis, a genetically and biochemically distinct form of programmed cell death, is characterized by iron-dependent accumulation of lipid peroxides. Ferroptosis is induced in cancer cells by inhibition of lipid peroxide quencher GPx4. System xc - imports cystine into cytosol for the biosynthesis of glutathione. Tumor cells that are resistant to chemotherapeutic drugs called ‘drug tolerant’ or ‘Persister’ cells which have distinct vulnerability towards iron mediated cell death or ferroptosis. Unfolded Protein Response (UPR) plays critical role for cancer cells to become drug tolerant. Tweaking the balance of UPR to make drug tolerant cells susceptible to Ferroptotic cell death could be an attractive therapeutic strategy. To decipher the emerging contribution of ER-stress in ferroptosis, we investigated the status of UPR following treatment of potent ferroptosis inducer RSL3 (Ras Selective Lethal) in colon cancer cells. We observed an overall up-regulation of UPR activators (ATF6, IRE1α and PERK) and their downstream effectors along with a marked overexpression of cystine-glutamate transporter (System xc -). To further delineate the contribution of particular UPR arm in modulating System xc - expression and subsequent ferroptosis, we made stable knock down cells of each UPR arm and discovered that PERK is selective and critical in inducing ferroptosis in colon cancer cells. Loss of PERK function not only promotes ferroptosis via increasing lipid peroxidation but also limits in vivo tumor growth in colon xenograft model. Further, we find that low PERK expression is associated with higher patient survival as per TCGA COLON CANCER (COAD) database. Overall, our experimental data indicate that PERK is a negative regulator of ferroptosis and genetic silencing of PERK sensitizes colon cancer cells to selective Ferroptotic cell death. Therefore, small molecule PERK inhibitors hold huge promise as novel therapeutics that can sensitize apoptosis resistant cancer cells towards Ferroptotic cell death. Citation Format: Krishan K. Saini, Priyank Chaturvedi, Ayushi Verma, Mushtaq A. Nengroo, Abhipsa Sinha, Akhilesh Singh, Sanjeev Meena, Muqtada A. Khan, Manish P. Singh, Dipak Datta. PERK arm of UPR selectively regulates ferroptosis in colon cancer cells by modulating the expression of system xc - (SLC7A11) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6249.

Alternaria solani, a plant pathogenic fungus causes significant economical losses of potato crop. The disease is controlled primarily through some traditional methods and most commonly via the application of chemical fungicides. Fungicides treatment is not protected as chemicals pollute environment, effect health vulnerability in humans and when these harmful chemicals enter into the food chain become hazardous to all living entities. Recent efforts have focused on developing environmentally safe, long-lasting, and effective biocontrol methods for the management of plant diseases. Present research focus on screening of crude and partially purified leaf extract of Thevetia peruviana for the presence of antifungal efficacy against Alternarai solani. It was observed that 100% alcoholic crude and alcoholic fraction of partially purified extract showed maximum inhibitory activity which is due to the presence of different secondary metabolites, revealed by phytochemical screening. Active column fraction (possess best antifungal activity against Alternaria solani) was subjected to Gas Chromatography-Mass Spectrometry (GS-MS) analysis. On the basis of peaks matching of GC-MS chromatogram with available data base showed the presence of benzoic acid and oxo-benzoate in active fraction of Thevetia peruviana leaf extract which is already known chemical among the phytochemicals described for antimicrobial activity. Further research on development of herbal formulation from the same would be very helpful environment friendly approach to manage concern crop disease., Highlights • Isolation of active principle compound was found maximum in Alcohol extract of Thevetia peruviana leaf extract. • Phytochemical tests suggest that Alkaloids, steroids, volatile oils, flavonoids, and tannins were found to be present in alcohol extract of Thevetia peruviana leaf extract. • In vitro assay of antifungal activity of all column fractions fraction no. F9 which exhibited most significant antifungal activity against the test fungus. • GC–MS analysis of column fraction showed the occurrence of total 1 constituent.

Stereoselective synthesis of twenty (three 12-, five 13- and twelve 14-membered) macrolides and seventeen functionalized 2,6-trans-disubstituted dihydropyran derivatives have been achieved. The key reactions include an Achmatowicz rearrangement, Ferrier-type alkynylation, Yamaguchi macrolactonization and Lindlar’s hydrogenation. Biological screening of the synthesised compounds showed moderate activity against human cancer cell-lines.

Ethnopharmacological relevance Medicinal plants used in traditional medicines are affordable, easily accessible, safer, less toxic and considered as a rich or efficient source of bioactive molecules for modern therapeutics. Artemisia nilagirica (AR) has a long history of use in Indian traditional medicine to combat a wide variety of diseases including cancer. Aim of the study Considering the vast potential of traditional healing plants to deliver safer, less toxic and efficient chemotherapeutics, we have examined anticancer activity of ethanolic extract, bioactive fractions and sub-fractions of AR against different human cancer cell lines along with their phytochemical analysis to understand the insights of novel anticancer activities for further preclinical studies. Materials and methods Fresh plant material of AR was procured from the wild, dried and ground. The grinded materials was extracted in ethanol (AR-01) and fractionated into butanol (AR-02), ethyl acetate (AR-03), hexane (AR-04) and water (AR-05). The cytotoxicity was evaluated against three different human cancer cell lines, i.e. colon (DLD-1), lung (A-549), and breast (MCF-7) using Sulforhodamine B (SRB) assay along with non-cancerous VERO cells as control and doxorubicin (DOX) as positive control. As we observed strong cytotoxicity of AR-03 and AR-04 fractions against tested cells and marked cytotoxic effects particularly in colon cancer cell lines, we further re-fractionated, AR-03 into (AR-03A, AR-03B, AR-03C, AR-03D, AR-03E) and AR-04 into (AR-04A, AR-04B, AR-04C) sub-fractions by column chromatography and investigated against the same panel of cell lines in addition to one more colon cancer cell line (HT-29). Phytochemical analysis was performed through HPLC-ESI-QTOF-MS/MS fragmentation. Results Ethyl acetate (AR-03) and hexane (AR-04) fractions were found to be the most cytotoxic against all the tested cell lines. Further, AR-03E and AR-04A sub-fractions were found more specific cytotoxic selectively against DLD-1 cancer cell lines at 100 µg/ml concentration. HPLC-ESI-QTOF-MS/MS determination revealed the presence of 17 compounds in AR-01. Among them, 4 compounds were reported for the first time in this species. However, 3 identified compounds (artemorin, β-santonin and caryophyllene oxide) in AR-03E sub-fraction were commonly present in each bioactive fraction and may be considered as potential and safest cytotoxic agents for anticancer activity. Conclusions Experimental evidences reported in this paper for anticancer activity validate the traditional wisdom of Artemisia nilagirica as an anticancer herbal drug. To our knowledge, this is our first novel observation of cytotoxicity and selectivity of ethyl acetate and hexane sub-fraction of AR-01 i.e. AR-03E and AR-04A respectively against DLD-1 human cancer cell lines. HPLC-ESI-QTOF-MS/MS determination attributes the identification of cytotoxic compounds which may be used for further preclinical studies.

Molecular hybridization of different pharmacophores to tackle both tumor growth and metastasis by a single molecular entity can be very effective and unique if the hybrid product shows drug-like properties. Here, we report synthesis and discovery of a novel small-molecule inhibitor of PP2A–β-catenin signaling that limits both in vivo tumor growth and metastasis. Our molecular hybridization approach resulted in cancer cell selectivity and improved drug-like properties of the molecule. Inhibiting PP2A and β-catenin interaction by selectively engaging PR55α-binding site, our most potent small-molecule inhibitor diminished the expression of active β-catenin and its target proteins c-Myc and Cyclin D1. Furthermore, it promotes robust E-cadherin upregulation on the cell surface and increases β-catenin–E-Cadherin association, which may prevent dissemination of metastatic cells. Altogether, we report synthesis and mechanistic insight of a novel drug-like molecule to differentially target β-catenin functionality via interacting with a particular subunit of PP2A. Mol Cancer Ther; 16(9); 1791–805. ©2017 AACR.

Therapy resistance by evasion of apoptosis is one of the hallmarks of human cancer. Therefore, restoration of cell death by non-apoptotic mechanisms is critical to successfully overcome therapy resistance in cancer. By rational drug design approach, here we try to provide evidence that subtle changes in the chemical structure of spisulosine completely switched its cytotoxic function from apoptosis to autophagy. Our most potent molecule (26b) in a series of 16 synthesized derivatives showed robust autophagic cell death in diverse cancer cells sparing normal counterpart. Compound 26b mediated lethal autophagy induction was confirmed by formation of characteristic autophagic vacuoles, LC3 puncta formation, upregulation of signature autophagy markers like Beclin and Atg family proteins. Altogether, we have detected novel autophagy inducer small molecule which can be tested further for drug discovery research.

Triple-negative breast cancers (TNBCs) are one of the most aggressive and complex forms of cancers in women. TNBCs are commonly known for their complex heterogeneity and poor prognosis. The present work aimed to develop a predictive 2D and 3D quantitative structure-activity relationship (QSAR) models against metastatic TNBC cell line. The 2D-QSAR was based on multiple linear regression analysis and validated by Leave-One-Out (LOO) and external test set prediction approach. QSAR model presented regression coefficient values for training set (

In this current work, the n-hexane fraction from an ethanolic extract of pulverized peel of Ipomoea batatas Lam was subjected to chromatographic fractionation. Consequently, the fractions were investigated for their anticancer potential using the Sulforhodamine-B assay. Chromatographic fractionation led to n-hexane sub-fractions with greater anticancer potential. The study highlights the peel of Ipomoea batatas Lam as a rich dietary source of natural anticancer molecules which may be developed into nutraceuticals or serve as new leads in anticancer therapy. Keywords: Ipomoea batatas; Chromatography; Fractionation; Anticancer; Sulforhodamine-B

In this study, we attempted the chemical simplification of Psammaplin (PsA), while retaining its activity in vitro. Inspired by the previous Structure Activity Relationship (SAR) studies on various PsA analogues and relying on the fact that oxime is metabolically unstable, we initially designed and synthesized a diverse library of PsA analogues and evaluated for cytotoxic activity. Among 32 compounds of Psammaplin analogues synthesized, the compound 10b was almost equally active as parent Psammaplin in vitro.

A bioassay-guided fractionation of an alcoholic extract from the peels of Ipomoea batatas Lam has been carried out. Sulforhodamine B and 2,2-diphenyl-1-picrylhydrazyl (DPPH) assays were used to evaluate the anticancer and antioxidant potential, respectively, while silica gel column chromatography (CC) was used to isolate compounds that were characterized using 1D- and 2D-NMR (Nuclear Magnetic Resonance) and mass spectrometry. The alcoholic extract was fractionated into n-hexane, ethyl acetate, n-butanol, and water. The n-hexane fraction which showed the most promising anticancer activity was further fractionated via silica gel CC into IB-F002A, IB-F002B, and IB-F002C. Of these, IB-F002C was the most active with IC50 values 24.75, 47.91, 52.37, 34.17, 46.07, and 25.89 μg/ml against breast, colon-1, colon-2, ovary, lung, and head/neck cancer cell lines, respectively. The bioassay-guided isolation from IB-F002C afforded a glucocerebroside, which showed 10.51%, 12.19%, 16.14%, and 34.05% inhibition of...

The rhizome of Hedychium spicatum has been widely used in traditional medicines. The present study deals with the evaluation of the cytotoxic potential of rhizome essential oils from four different regions of the Western Himalaya (India) along with comparative correlation analysis to characterise the bioactive cytotoxic component. The essential oils were coded as MHS-1, MHS-2, MHS-3 and MHS-4, and characterised using GC-FID and GC–MS. The main volatile compounds identified were 1,8-cineol, eudesmol, cubenol, spathulenol and α-cadinol. In vitro cytotoxic activities were assessed against human cancer cell lines such as, the lung (A549), colon (DLD-1, SW 620), breast (MCF-7, MDA-MB-231), head and neck (FaDu), and cervix (HeLa). MHS-4 is significantly active in comparison to other samples against all cancer cell lines. Sample MHS-4 has major proportion of monoterpene alcohol mainly 1,8-cineol. Principal components analysis was performed for the experimental results and all four samples were clustered according to their percentage inhibition at different doses.

As per WHO estimates, 80% of people around the world use medicinal plants for the cure and prevention of various diseases including cancer owing to their easy availability and cost effectiveness.Eclipta albahas long been used in Ayurveda to treat liver diseases, eye ailments, and hair related disorders. The promising medicinal value ofE. albaprompted us to study the antioxidant, nontoxic, and anticancer potential of its alcoholic extract. In the current study, we evaluated thein vitrocytotoxic and antioxidant effect of the alcoholic extract ofEclipta alba(AEEA) in multiple cancer cell lines along with control. We have also evaluated its effect on differentin vivotoxicity parameters. Here, we found that AEEA was found to be most active in most of the cancer cell lines but it significantly induced apoptosis in human breast cancer cell lines by disrupting mitochondrial membrane potential and DNA damage. Moreover, AEEA treatment inhibited migration in both MCF 7 and MDA-MB-231 cells in a dose dependent manner. Further, AEEA possesses robustin vitroantioxidant activity along with high total phenolic and flavonoid contents. In summary, our results indicate thatEclipta albahas enormous potential in complementary and alternative medicine for the treatment of cancer.

Although tumor heterogeneity is widely accepted, the existence of cancer stem cells (CSCs) and their proposed role in tumor maintenance has always been challenged and remains a matter of debate. Recently, a path-breaking chapter was added to this saga when three independent groups reported the in vivo existence of CSCs in brain, skin and intestinal tumors using lineage-tracing and thus strengthens the CSC concept; even though certain fundamental caveats are always associated with lineage-tracing approach. In principle, the CSC hypothesis proposes that similar to normal stem cells, CSCs maintain self renewal and multilineage differentiation property and are found at the central echelon of cellular hierarchy present within tumors. However, these cells differ from their normal counterpart by maintaining their malignant potential, alteration of genomic integrity, epigenetic identity and the expression of specific surface protein profiles. As CSCs are highly resistant to chemotherapeutics, they are thought to be a crucial factor involved in tumor relapse and superficially appear as the ultimate therapeutic target. However, even that is not the end; further complication is attributed by reports of bidirectional regeneration mechanism for CSCs, one from their self-renewal capability and another from the recently proposed concept of dynamic equilibrium between CSCs and non-CSCs via their interconversion. This phenomenon has currently added a new layer of complexity in understanding the biology of tumor heterogeneity. In-spite of its associated controversies, this area has rapidly emerged as the center of attention for researchers and clinicians, because of the conceptual framework it provides towards devising new therapies.

The stereoselective synthesis of Jaspine B has been achieved from easily available ( S )-Garner’s aldehyde. The trisubstituted tetrahydrofuran core of Jaspine B was constructed by utilizing a diastereoselective iodocyclization as the key step. Deiodination and debenzylation were performed in a single step by using n -Bu 3 SnH and ABCN as a conjugate catalyst system. The in vitro cytotoxicity of compounds 1 and 1a against 3 human cancer cell lines-A549 (lung), MCF7 (breast), and KB (oral); and a non-cancer cell line (NIH3T3) was determined by sulphorhodamine B based assay.

Existing cancer therapies are often associated with drug resistance and toxicity, which results in poor prognosis and recurrence of cancer. This necessitates the identification and development of novel therapeutics against existing as well as novel cellular targets. In this study, a novel class of Benzocoumarin-Stilbene hybrid molecules were synthesized and evaluated for their antiproliferative activity against various cancer cell lines followed by in vivo antitumor activity in a mouse model of cancer. The most promising molecule among the series, i.e. compound (E)-4-(3,5-dimethoxystyryl)-2H-benzo[h]chromen-2-one (19) showed maximum antiproliferative activity in breast cancer cell lines (MDA-MB-231 and 4T1) and decreased the tumor size in the in-vivo 4T1 cell-induced orthotopic syngeneic mouse breast cancer model. The mechanistic studies of compound 19 by various biochemical, cell biology and biophysical approaches suggest that the compound binds to and inhibits the human DNA ligase I enzyme activity that might be the cause for significant reduction in tumor growth and may constitute a promising next-generation therapy against breast cancers.

As per WHO estimates, 80% of people around the world use medicinal plants for the cure and prevention of various diseases including cancer owing to their easy availability and cost effectiveness. Eclipta alba has long been used in Ayurveda to treat liver diseases, eye ailments, and hair related disorders. The promising medicinal value of E. alba prompted us to study the antioxidant, nontoxic, and anticancer potential of its alcoholic extract. In the current study, we evaluated the in vitro cytotoxic and antioxidant effect of the alcoholic extract of Eclipta alba (AEEA) in multiple cancer cell lines along with control. We have also evaluated its effect on different in vivo toxicity parameters. Here, we found that AEEA was found to be most active in most of the cancer cell lines but it significantly induced apoptosis in human breast cancer cell lines by disrupting mitochondrial membrane potential and DNA damage. Moreover, AEEA treatment inhibited migration in both MCF 7 and MDA-MB-231 cells in a dose dependent manner. Further, AEEA possesses robust in vitro antioxidant activity along with high total phenolic and flavonoid contents. In summary, our results indicate that Eclipta alba has enormous potential in complementary and alternative medicine for the treatment of cancer.

Betula utilis, also known as Himalayan silver birch has been used as a traditional medicine for many health ailments like inflammatation, HIV, renal and bladder disorders as well as many cancers from ages. Here, we performed bio-guided fractionation of Betula utilis Bark (BUB), in which it was extracted in methanol and fractionated with hexane, ethyl acetate, chloroform, n-butanol and water. All six fractions were evaluated for their in-vitro anticancer activity in nine different cancer cell lines and ethyl acetate fraction was found to be one of the most potent fractions in terms of inducing cytotoxic activity against various cancer cell lines. By utilizing column chromatography, six triterpenes namely betulin, betulinic acid, lupeol, ursolic acid (UA), oleanolic acid and β-amyrin have been isolated from the ethyl acetate extract of BUB and structures of these compounds were unraveled by spectroscopic methods. β-amyrin and UA were isolated for the first time from Betula utilis. Isolated triterpenes were tested for in-vitro cytotoxic activity against six different cancer cell lines where UA was found to be selective for breast cancer cells over non-tumorigenic breast epithelial cells (MCF 10A). Tumor cell selective apoptotic action of UA was mainly attributed due to the activation of extrinsic apoptosis pathway via up regulation of DR4, DR5 and PARP cleavage in MCF-7 cells over non-tumorigenic MCF-10A cells. Moreover, UA mediated intracellular ROS generation and mitochondrial membrane potential disruption also play a key role for its anti cancer effect. UA also inhibits breast cancer migration. Altogether, we discovered novel source of UA having potent tumor cell specific cytotoxic property, indicating its therapeutic potential against breast cancer.

The anticancer potential of Xylopia aethiopica fruit extract (XAFE), and the mechanism of cell death it elicits, was investigated in various cell lines. Treatment with XAFE led to a dose-dependent growth inhibition in most cell lines, with selective cytotoxicity towards cancer cells and particularly the human cervical cancer cell line C-33A. In this study, apoptosis was confirmed by nuclear fragmentation and sub-G(0)/G(1) phase accumulation. The cell cycle was arrested at the G(2)/M phase with a decreased G(0)/G(1) population. A semi-quantitative gene expression study revealed dose-dependent up-regulation of p53 and p21 genes, and an increase in the Bax/Bcl-2 ratio. These results indicate that XAFE could be a potential therapeutic agent against cancer since it inhibits cell proliferation, and induces apoptosis and cell cycle arrest in C-33A cells.

Objective: The present study was focused to screen traditionally used Barleria prionitis for anticancer effects against various cell lines and antimicrobial effect against various pathogenic strains of bacteria and fungi. Methods: Extraction of Barleria prionitis leaves in ethanol was done by the Soxhlet method. After extraction, phytochemical estimation of these seven secondary metabolites like alkaloids, flavonoids, anthraquinones, saponins, terpenoids, tannins, and cardiac glycosides was done as per the protocols of Kokate. Minimum Inhibitory Concentration (MIC) effect of Barleria leaf ethanol (BLE) was done by the dilution method on five bacterial and five fungal strains. Further analysis (anticancer activity) was done with SRB (Sulphorhodamine B) assay. Statistical analysis of antimicrobial and anticancer activity was done by using MS Excel 2007 to±standard deviation and student t-test. Results: Barleria leaf extract with ethanol is a non-polar solvent extract and considered as the best solvent to extract the maximum number of secondary metabolites like alkaloids, saponins, flavonoids, and tannins. BLE extract gave excellent MIC (Minimum Inhibitory Concentration) effects against pathogenic bacteria and pathogenic fungal strains. BLE had highly effective activity against Pseudomonas aeruginosa with 1.25 mg MIC, the OD value of the sample was 0.02±0.0005 (±SD) with 0.0211-0.0245 range. MIC against fungal strains had effective activity against Candida vaginitis with 6.25 mg, the OD value of the sample was 0.02±0.0003 (±SD) with 0.0213-0.0232 range. BLE extract had given more than 70% inhibition against breast cell lines (MCF-7) and 75.16% inhibition of DLD1 cell lines; it was near to Doxorubicin antibiotic (81%). Breast metastatic cell line (MDMAMB-468) was found 60% inhibited with BLE extract and there was a great difference in the results of Doxorubicin. Out of six experimented cell lines, BLE gave very good inhibition for two cell lines, i.e. Breast (MCF-7) and Colon cell lines (DLD-1). Conclusion: BLE extract had shown the best antimicrobial and antifungal effect, against Pseudomonas aeruginosa and Candida vaginitis respectively. BLE also showed an anticancer effect against Lung cell lines (A549), Breast cancer cell line (MCF-7), Breast metastatic cell line (MDMAMB-468), Colon cell line (DLD-1) and lung metastatic cell line (NCIH358) at a statistically significant level ( p=

A series of 2-(pyrimidin-2-yl)-1-phenyl-2,3,4,9-tetrahydro-1 H -β-carboline derivatives has been synthesized and evaluated for antileishmanial activity against Leishmania donovani . Compound 8 exhibited best antileishmanial activity with IC 50 value of 1.93 μg/ml against amastigotes, high selectivity index, and was more active than reference drugs sodium stilbogluconate and pentamidine.

Major challenges for current therapeutic strategies against breast cancer are associated with drug-induced toxicities. Considering the immense potential of bioactive phytochemicals to deliver non-toxic, efficient anti-cancer therapeutics, we performed bio-guided fractionation of Eclipta alba extract and discovered that particularly the chloroform fraction of Eclipta alba (CFEA) is selectively inducing cytotoxicity to breast cancer cells over non-tumorigenic breast epithelial cells. Our unbiased mechanistic hunt revealed that CFEA specifically activates the intrinsic apoptotic pathway by disrupting the mitochondrial membrane potential, upregulating Hsp60 and downregulating the expression of anti-apoptotic protein XIAP. By utilizing Hsp60 specific siRNA, we identified a novel pro-apoptotic role of Hsp60 and uncovered that following CFEA treatment, upregulated Hsp60 is localized in the endoplasmic reticulum (ER). To our knowledge, this is the first evidence of ER specific localization of Hsp60 during cancer cell apoptosis. Further, our LC-MS approach identified that luteolin is mainly attributed for its anti-cancer activities. Moreover, oral administration of CFEA not only offers potential anti-breast cancer effects in-vivo but also mitigates tumor induced hepato-renal toxicity. Together, our studies offer novel mechanistic insight into the CFEA mediated inhibition of breast cancer and may potentially open up new avenues for further translational research.

Human DNA ligases are enzymes that are indispensable for DNA replication and repair processes. Among the three human ligases, ligase I is attributed to the ligation of thousands of Okazaki fragments that are formed during lagging strand synthesis during DNA replication. Blocking ligation therefore can lead to the accumulation of thousands of single strands and subsequently double strand breaks in the DNA, which is lethal for the cells. The reports of the high expression level of ligase I protein in several cancer cells (versus the low ligase expression level and the low rate of division of most normal cells in the adult body) support the belief that ligase I inhibitors can target cancer cells specifically with minimum side effects to normal cells. Recent publications showing exciting data for a ligase IV inhibitor exhibiting antitumor activity in mouse models also strengthens the argument for ligases as valid antitumor targets. Keeping this in view, we performed a pharmacophore-based screening for potential ligase inhibitors in the Maybridge small molecule library and procured some of the top-ranking compounds for enzyme-based and cell-based in vitro screening. We report here the identification of novel ligase I inhibitors with potential anticancer activity against a colon cancer cell line.

A series of novel β-carboline based chalcones was synthesized and evaluated for their cytotoxic activity against a panel of human cancer cell lines. Among them we found that two of the compounds 7c and 7d, showed marked anti-proliferative activity in a panel of solid tumor cell lines with highest effect in breast cancer. The compounds 7c and 7d showed an IC50 of 2.25 and 3.29 μM, respectively against human breast cancer MCF-7 cell line. Further, the compound 7c markedly induced DNA fragmentation and apoptosis in breast cancer cells.

Although tumor heterogeneity is widely accepted, the existence of cancer stem cells (CSCs) and their proposed role in tumor maintenance has always been challenged and remains a matter of debate. Recently, a path-breaking chapter was added to this saga when three independent groups reported the in vivo existence of CSCs in brain, skin and intestinal tumors using lineage-tracing and thus strengthens the CSC concept; even though certain fundamental caveats are always associated with lineage-tracing approach. In principle, the CSC hypothesis proposes that similar to normal stem cells, CSCs maintain self renewal and multilineage differentiation property and are found at the central echelon of cellular hierarchy present within tumors. However, these cells differ from their normal counterpart by maintaining their malignant potential, alteration of genomic integrity, epigenetic identity and the expression of specific surface protein profiles. As CSCs are highly resistant to chemotherapeutics, they are thought to be a crucial factor involved in tumor relapse and superficially appear as the ultimate therapeutic target. However, even that is not the end; further complication is attributed by reports of bidirectional regeneration mechanism for CSCs, one from their self-renewal capability and another from the recently proposed concept of dynamic equilibrium between CSCs and non-CSCs via their interconversion. This phenomenon has currently added a new layer of complexity in understanding the biology of tumor heterogeneity. In-spite of its associated controversies, this area has rapidly emerged as the center of attention for researchers and clinicians, because of the conceptual framework it provides towards devising new therapies.

A stereoselective route for the total synthesis of anticancer marine natural product (+)-varitriol (1) is detailed herein. The impressive biological activity and interesting structural features of natural (+)-varitriol fuelled us to undertake the synthesis of some higher analogues (1a–j) of this molecule. The key features of the synthetic strategy include one-pot Wittig olefination followed by a highly diastereoselective oxa-Michael addition to assemble stereochemically pure tetrasubstituted THF moiety of the natural varitriol and olefin cross metathesis to couple the aromatic part with tetrasubstituted THF moiety. The total synthesis of title natural product is efficient with 21.8% overall yield for 9 linear steps from D-ribose and thus facilitates the more scaled-up practical route for the synthesis of 1 and its analogues as well. The synthetic (+)-varitriol (1) and its analogues were screened for their cytotoxicity. The present synthetic approach paves the way for preparation of numerous analogues of the title natural product for drug development.

The synthetic pathway to β-carbolines (V) and (VII) involves oxidation of educt (I) to its sulfone followed by nucleophilic substitution of the formed mesyl group with tryptamine (II).

The anticancer potential of Xylopia aethiopica fruit extract (XAFE), and the mechanism of cell death it elicits, was investigated in various cell lines. Treatment with XAFE led to a dose-dependent growth inhibition in most cell lines, with selective cytotoxicity towards cancer cells and particularly the human cervical cancer cell line C-33A. In this study, apoptosis was confirmed by nuclear fragmentation and sub-G(0)/G(1) phase accumulation. The cell cycle was arrested at the G(2)/M phase with a decreased G(0)/G(1) population. A semi-quantitative gene expression study revealed dose-dependent up-regulation of p53 and p21 genes, and an increase in the Bax/Bcl-2 ratio. These results indicate that XAFE could be a potential therapeutic agent against cancer since it inhibits cell proliferation, and induces apoptosis and cell cycle arrest in C-33A cells.

A series of tetrahydro-beta-carbolines and 1,3,5-triazine hybrids have been synthesized and evaluated for their cytotoxicity against a panel of eight human cancer cell lines and normal human fibroblasts (NIH3T3). It led us to discovery of racemic compounds 69, 71 and 75, which are selectively cytotoxic towards KB (oral cancer) cell line with IC50 values of 105.8, 664.7 and 122.2 nM, respectively; while their enantiopure forms are less active and not selective. Enantiopure compound 42 showed 2.5 times more selectivity towards MCF7 cells over normal fibroblast NIH3T3 cells with an IC50 value of 740 nM, also arrests cell cycle in G1 phase and induces apoptosis in MCF7 and MDA MB231 cell lines.

Summary Our study demonstrates that staurosporine (STS), a protein kinase inhibitor from Streptomyces sp., induces apoptosis in human papillomavirus positive oral carcinoma cells (KB) in a dose dependent manner. Growth inhibition studies revealed an IC 50 value of approximately 100 nM. STS induced marked nuclear fragmentation and inter-nucleosomal cleavage compared to untreated cells. It also caused dose dependent disruption of mitochondrial membrane potential and activation of caspase-3, indicating involvement of mitochondria-mediated cell death signaling in KB cell apoptosis. We found time-dependent arrest of the KB cells at G2/M phase of cell cycle. Using fluorescence microscopy, we have further shown that STS treatment disrupts microtubules and reorganizes F-actin after 6 h exposure. Taken together, our results suggest that STS induces mitochondria-mediated KB cell apoptosis at G2/M phase by altering cell cytoskeletal network.