Ethnomedicinal values of Boerhaavia diffusa L. as a panacea against multiple human ailments: a state of art review.

Ethnopharmacological relevance: Therapeutic botanicals (plants and derivatives) are in use since antiquity for various health ailments. The ethnic community is the repository of the information, the multifactorial therapeutic applications of which may often need scientific validation. The spreading hogweed or Boerhaavia diffusa L., also known as Punarnava, is a reassuring medicinal herb with diverse pharmacological benefits. It is used in Ayurveda in Asia and Africa as a rejuvenator or "Rasayan" for its excellent antiaging and antioxidant properties. Aim: The study aimed at compiling the state-of-art knowledge of the medicinal benefits of Boerhaavia diffusa L. and unraveling the unexplored commercially useful bioactive constituents by establishing their possible pharmacological benefits. Methods: The data from published literature, confined to pharmacological manifestations of various phytocomponents of Boerhaavia diffusa L. or its parts like root, leaf and stem were extracted from scientific databases, Google, Science Direct, PubMed, etc. using its antifungal, antibacterial, anticancer, anti-inflammatory, antidiabetic, hepatoprotective, cardioprotective, renoprotective, antifertility benefits and molecular docking study as search strings and keywords. Further, the reported in silico studies for bioactivity and bioavailability are detailed. Results: The botanicals possess numerous bioactive compounds, the most widely reported ones being phenolic (punarnavoside, trans-caftaric acid, boerhavic acid), rotenoid (boeravinones A-J), flavonoid (borhaavone, quercetin, kaempferol), isoflavonoid (2'-O-methyl abronisoflavone), alkaloid (punarnavine), steroid (boerhavisterol, ß-Ecdysone), anthracenes and lignans (liriodendrin, syringaresinol mono-ß-D-glucoside). Some of the reported reassuring benefits of their purified forms or even the crude extracts are antidiabetic, antimicrobial, anticancer, antioxidant, anti-inflammatory, hepatoprotective, renoprotective, cardioprotective, antifertility, etc. Conclusion: The article provides an extensive study on such pharmacological utility to support the ethnomedicinal use of Boerhaavia diffusa L. and propose possible mechanism of the various bioactive compounds in optimising metabolic dysfunctions, healing and protecting vital body organs, often related to the magnificent antioxidant property of this ayurvedic panacea. Further, establishing specific roles of its yet-to-explore bioactive constituents for diverse pharmacological applications is suggested.

Computational Approach to Combat COVID-19 Infection: Emerging Tools for Accelerating Drug Research.

BACKGROUND: The process of drug discovery and development is expensive, complex, timeconsuming, and risky. There are different techniques involved in the process of drug development, including random screening, computational approaches, molecular manipulation, and serendipitous research. Among these methods, the computational approach is considered an efficient strategy to accelerate and economize the drug discovery process. OBJECTIVE: This approach is mainly applied in various phases of the drug discovery process, including target identification, target validation, lead identification, and lead optimization. Due to the increase in the availability of information regarding various biological targets of different disease states, computational approaches such as molecular docking, de novo design, molecular similarity calculation, virtual screening, pharmacophore-based modeling, and pharmacophore mapping have been applied extensively. METHODS: Various drug molecules can be designed by applying computational tools to explore the drug candidates for the treatment of Coronavirus infection. The World Health Organization announced the coronavirus disease as COVID-19 and declared it a global pandemic on 11 February 2020. Therefore, it is thought of interest to the scientific community to apply computational methods to design and optimize the pharmacological properties of various clinically available and FDA-approved drugs such as remdesivir, ribavirin, favipiravir, oseltamivir, ritonavir, arbidol, chloroquine, hydroxychloroquine, carfilzomib, baraticinib, prulifloxacin, etc., for effective treatment of COVID-19 infection. RESULTS: Further, various survey reports suggest that extensive studies are carried out by various research communities to find out the safety and efficacy profile of these drug candidates. CONCLUSION: This review is focused on the study of various aspects of these drugs related to their target sites on the virus, binding interactions, physicochemical properties, etc.

Natural therapeutics for urinary tract infections-a review.

BACKGROUND: The recurrence of the urinary tract infections (UTI), following the antibiotic treatments suggests the pathogen's resistance to conventional antibiotics. This calls for the exploration of an alternative therapy. MAIN BODY: The anti-uropathogenic and bactericidal activity of many plant extracts was reported by many researchers, which involves only preliminary antibacterial studies using different basic techniques like disk diffusion, agar well diffusion, or minimum inhibitory concentration (MIC) of the crude plant extracts, but reports on the specific action of the phytoconstituents against uropathogens are limited. Vaccinium macrocarpon Aiton (cranberry) is the best-studied home remedy for UTI. Some evidences suggest that proanthocyanins present in cranberry, prevent bacteria from adhering to the walls of the urinary tract, subsequently blocking the further steps of uropathogenesis. Probiotics such as Lactobacillus and Bifidobacterium are beneficial microorganisms that may act by the competitive exclusion principle to defend against infections in the urogenital tracts. Reports on potential vaccine agents and antibodies targeting the different toxins and effecter proteins are still obscure except uropathogenic E. coli. CONCLUSION: This review highlights some of the medicinal herbs used by aborigines to prevent or treat acute or chronic urinary tract infections, botanicals with established urobactericidal activity, clinical trials undertaken to compare the efficacy of cranberry products in UTI prevention, and other natural therapeutics reported for UTI.

Nanoquinacrine sensitizes 5-FU-resistant cervical cancer stem-like cells by down-regulating Nectin-4 via ADAM-17 mediated NOTCH deregulation.

PURPOSE: Cervical cancer is a major cause of cancer-related death in women world-wide. Although the anti-metabolite 5-FU is widely used for its treatment, its clinical utility is limited due to the frequent occurrence of drug resistance during metastasis. Cancer stem-like cells (CSCs), present in the heterogeneous population of CC cells, are thought to contribute to this resistance. Nectin-4, a CSC marker, is known to play an important role in the cellular aggressiveness associated with metastatic CC. This study was designed to assess the role of Nectin-4 in the acquisition of 5-FU resistance by metastatic CC cells, including its relation to the NOTCH signalling pathway. METHODS: 5FU-resistant CC cell lines were deduced from ME-180 and SiHA cells by continuous exposure to a single concentration of 5-FU. Thymidylate synthase (TS) positive cells were isolated from the 5-FU resistant cells, after which a metastatic model was developed. The role of Nectin-4 in the sensitization of 5-FU resistant metastatic CC cells upon incubation with Nano-formulated Quinacrine (NQC) was investigated using multiple bioassays including MTT, FACS, ELISA, immunoflurescence, Western blotting, comet and in vivo plasmid-based short patch and long patch base excision repair assays. RESULTS: We found that the expression level of Nectin-4, as well as that of other CSC markers (Oct-4, ß-catenin, SOX2) and representative NOTCH signalling components (NOTCH-1, Jagged-1, γ-secretase, ADAM-17) were elevated in the 5-FU resistant metastatic cells compared to those in control cells. Increased nuclear translocation of Nectin-4 and increased proliferation and invasion rates were observed after culturing the metastatic cells under hypoxic conditions. Treatment with NQC inhibited the nuclear translocation of Nectin-4 and decreased the proliferation and invasion rates of the cells by inhibiting the induction of base excision repair (BER) pathway components and ADAM-17 expression levels. After combination treatment of Nectin-4 overexpressing metastatic CC cells with a specific ADAM-17 inhibitor (GW280264) and NQC, a decreased Nectin-4 expression, without alterations in BER and/or other NOTCH pathway components, was noted. CONCLUSION: Our data indicate that Nectin-4 may play a prominent role in 5-FU resistance of metastatic CC cells and that NQC sensitizes these cells by Nectin-4 deregulation through ADAM-17 inhibition, a major component of the NOTCH signalling pathway.

The soluble nectin-4 ecto-domain promotes breast cancer induced angiogenesis via endothelial Integrin-ß4.

Cancer stem cells secrete diffusible factors into the microenvironment that bind to specific endothelial cell receptors and initiate an angiogenesis cascade. Tumor-induced angiogenesis is an important parameter of tumorigenesis and is critical for tumor growth and metastasis. A pvrl-4 encoded gene, NECTIN-4, has potential roles in cancer cell growth and aggressiveness, and it is only expressed in cancer cells. There is evidence that nectin-4 plays a role in tumorigenesis, but the function of nectin-4 in tumor angiogenesis has lacked thorough evidence of mechanism. Using highly metastatic breast cancer cells and human umbilical vein endothelial cells (HUVECs), we have developed an excellent angiogenesis model and systematically studied the contribution of nectin-4 to angiogenesis. We also provide in-depth in ovo, in vivo and in vivo evidence that nectin-4 causes angiogenesis. Following hypoxia, metastatic breast cancer stem cells (mBCSCs) driven ADAM-17 expression causes the shedding of the ecto-domain of nectin-4 into the microenvironment, which physically interacts with integrin-ß4 specifically on endothelial cells. This interaction promotes angiogenesis via the Src, PI3K, AKT, iNOS pathway and not by Phospho-Erk or NF-κß pathways. In vitro, in ovo and in vivo induction and abrogation of an angiogenesis cascade in the presence and absence of the nectin-4 ecto-domain, respectively, confirms its role in angiogenesis. Thus, disrupting the interaction between nectin-4 ecto-domain and integrin-ß4 may provide a means of targeting mBCSC-induced angiogenesis.

Metallic gold and bioactive quinacrine hybrid nanoparticles inhibit oral cancer stem cell and angiogenesis by deregulating inflammatory cytokines in p53 dependent manner.

Complete eradication of aggressive oral cancer remains a challenge due to the presence of CSCs. They resist conventional chemotherapeutic agents due to their self-renewal, drug efflux, and efficient DNA repair capacity. Here, we formulated a hybrid-nanoparticle (QAuNP) using quinacrine and gold and characterized/investigated its anti-angiogenic and anti-metastatic effect on OSCC-CSCs. QAuNP significantly inhibited cellular proliferation, caused apoptosis in vitro, and disrupted angiogenesis in vivo and tumor regression in xenograft mice model. It not only inhibited crucial angiogenic markers Ang-1, Ang-2 and VEGF but also depleted MMP-2 in H-357-PEMT cells in a p53 and p21-dependent manner. QAuNP also increased the ROS and NO generation in OSCC-CSCs and reduced the mitochondrial membrane potential. It altered the level of inflammatory cytokines IL-6, IL-1ß, TNF-α and metastasis-associated markers (CD-44, CD-133) in H-357-PEMT and CM-treated endothelial cells (HUVEC) in p53/p21-dependent manner. Therefore, QAuNP will be a useful therapeutic agent against metastatic OSCC.

Enzyme-linked immunosorbent assay for group A Streptococcal anti-DNase B in human sera, using recombinant proteins - Comparison to the DNA methyl green micromethod.

Among the four known Streptococcal nucleases comprising of DNase A, B, C and D; DNase B is the most common, and determination of the levels of antibody to DNase B (ADB) is often used to confirm a clinical diagnosis of Streptococcus pyogenes/group A Streptococcal (GAS) infection. The commonly used assays for antibodies that neutralize DNase B or streptolysin O activity use partially purified antigens that often fail to detect antibody changes subsequent to culture documented infections. Therefore, an enzyme-linked immunosorbent assay (ELISA) was developed employing his-tagged recombinant DNase B as plate antigen for comparison to the commonly used DNA methyl green micromethod (DMGM). DNAs from various Streptococcal species were screened for presence of dnaseB gene by PCR. Measurements of ADB in sera collected from subjects belonging to different ages, and ethnic groups were used to compare the two methods. dnaseB was not detected by PCR in DNA samples isolated from different strains of group B (GBS), C (GCS) and G (GGS) Streptococci. The ADB based ELISA proved to be highly sensitive and more responsive to changes in antibody concentration than DMGM. Use of recombinant DNase B eliminates the variability associated with the enzyme, partially purified from Streptococcal culture supernatants from various commercial sources and may provide a more reliable source of antigen to a wider group of laboratories concerned with GAS diagnosis.

TRAIL enhances quinacrine-mediated apoptosis in breast cancer cells through induction of autophagy via modulation of p21 and DR5 interactions.

PURPOSE: Previously, we reported that quinacrine (QC) may cause apoptosis in breast and colon cancer cells by activating the death receptor 5 (DR5), resulting in autophagic cell death through p21 modulation. Here, we systematically evaluated the combined role of p21 and DR5 and their crosstalk in QC-mediated autophagy and apoptosis in breast cancer cells using in vitro and in vivo models. METHODS: Multiple breast cancer-derived cell lines (MCF-7, ZR-75-1, T47D, MDA-MB-231 and MCF-10A-Tr) and a mouse xenograft model were used. Also, multiple assays, including Western blotting, immunoprecipitation, staining for autophagy and apoptosis, gene silencing, hematoxylin and eosin staining, immunohistochemistry, cell viability assessment, fluorescence imaging and cell sorting were used. RESULTS: We found that QC activates p21 and DR5 in combination with the apoptosis inducer TRAIL in the breast cancer-derived cells tested. Combined TRAIL and QC treatment increased autophagy and apoptosis by increasing the interaction between, and co-localization of, p21 and DR5 in the death-inducing signaling complex (DISC). We found that this combination also inhibited the mTOR/PI3K/AKT signaling cascade and modulated reactive oxygen species (ROS) and nitric oxide (NO) production. Reductions in autophagy and apoptosis in DR5-knockout cells and a lack of change in p21-DR5-silenced cells were noted after TRAIL + QC treatment. This result explains dependence of the death (autophagy and apoptosis) cascade on these two key regulatory proteins. In addition, we found in an in vivo mouse xenograft model that increased expression and enhanced co-localization of p21 and DR5 after TRAIL + QC treatment supported a joint regulatory role of these proteins in the co-prevalence of autophagy and apoptosis. CONCLUSION: Our data suggest that a combined treatment of TRAIL and QC causes cell death in breast cancer-derived cells via autophagy and apoptosis by increasing the interaction of p21 and DR5, as indicated by both in vitro and in vivo studies.

Mild cold induced thermogenesis: are BAT and skeletal muscle synergistic partners?

There are two well-described thermogenic sites; brown adipose tissue (BAT) and skeletal muscle, which utilize distinct mechanisms of heat production. In BAT, mitochondrial metabolism is the molecular basis of heat generation, while it serves only a secondary role in supplying energy for thermogenesis in muscle. Here, we wanted to document changes in mitochondrial ultrastructure in these two tissue types based upon adaptation to mild (16°C) and severe (4°C) cold in mice. When reared at thermoneutrality (29°C), mitochondria in both tissues were loosely packed with irregular cristae. Interestingly, adaptation to even mild cold initiated ultrastructural remodeling of mitochondria including acquisition of more elaborate cristae structure in both thermogenic sites. The shape of mitochondria in the BAT remained mostly circular, whereas the intermyofibrilar mitochondria in the skeletal muscle became more elongated and tubular. The most dramatic remodeling of mitochondrial architecture was observed upon adaptation to severe cold. In addition, we report cold-induced alteration in levels of humoral factors: fibroblast growth factor 21 (FGF21), IL1α, peptide YY (PYY), tumor necrosis factor α (TNFα), and interleukin 6 (IL6) were all induced whereas both insulin and leptin were down-regulated. In summary, adaptation to cold leads to enhanced cristae formation in mitochondria in skeletal muscle as well as the BAT. Further, the present study indicates that circulating cytokines might play an important role in the synergistic recruitment of the thermogenic program including cross-talk between muscle and BAT.

Etoposide and doxorubicin enhance the sensitivity of triple negative breast cancers through modulation of TRAIL-DR5 axis.

Death receptor 5 (DR5) is an important target for development of anticancer agents against triple-negative breast cancer (TNBC). Recently, we reported the molecular level details for the modulation of TRAIL-DR5 axis by quinacrine (QC) in breast cancer cells. In this work, the DR5 mediated anticancer potential of topoisomerase inhibitor etoposide (ET) and doxorubicin (DOX) against TNBC has been evaluated. ET and DOX enhanced the DR5 expression in TNBC cells, whereas non-topoisomerase inhibitors pifithrin-α (PIF) and dexamethasone (DEX) failed to do so. In the TRAIL pre-treated cells, ET and DOX induced higher apoptosis, indicating their synergistic effect with TRAIL. The molecular docking and molecular dynamics studies showed their ability to stabilize the TRAIL-DR5 complex, whereas PIF and DEX failed to do so. The binding energy for TRAIL-DR5 complexation in the ternary complexes containing ET (-111.08 kcal/mol) and DOX (-76.35 kcal/mol) were higher than reported binding energy of binary complex (-53.70 kcal/mol). The in silico and in vitro mutational studies highlighted the importance of DR5 residue SerB68 in mediating the receptor-drug interaction. ET and DOX failed to enhance apoptosis in DR5 knockdown (DR5-KD) cells. On the other hand, TRAIL+ET exhibited induction of DR5 and subsequent apoptosis in WT-DR5 overexpressed DR5-KD cells, by modulating the mitochondrial intrinsic apoptosis cascade. An induction of apoptosis and DR5 expression was noticed in xenograft mice and in TNBC patient-derived metastatic cells after TRAIL+ET treatment. Thus, data suggests ET and DOX act as DR5 agonistic ligands and enhance the cellular apoptosis in TNBC.

Nanoquinacrine caused apoptosis in oral cancer stem cells by disrupting the interaction between GLI1 and ß catenin through activation of GSK3ß.

Presences of cancer stem cells (CSCs) in a bulk of cancer cells are responsible for tumor relapse, metastasis and drug resistance in oral cancer. Due to high drug efflux, DNA repair and self-renewable capacity of CSCs, the conventional chemotherapeutic agents are unable to kill the CSCs. CSCs utilizes Hedgehog (HH-GLI), WNT-ß catenin signalling for its growth and development. GSK3ß negatively regulates both the pathways in CSCs. Here, we have shown that a nano-formulated bioactive small molecule inhibitor Quinacrine (NQC) caused apoptosis in oral cancer stem cells (OCSCs; isolated from different oral cancer cells and oral cancer patient derived primary cells) by down regulating WNT-ß catenin and HH-GLI components through activation of GSK3ß. NQC activates GSK3ß in transcriptional and translational level and reduces ß catenin and GLI1 as well as downstream target gene of both the pathways Cyclin D1, C-Myc. The transcription factor activity of both the pathways was also reduced by NQC treatment. GSK3ß, ß catenin and GLI1 interacts with each other and NQC disrupts the co-localization and interaction between ß catenin and GLI1 in OCSCs in a dose dependent manner through activation of GSK3ß. Thus, data suggest NQC caused OCSCs death by disrupting the crosstalk between ß catenin and GLI1 by activation of GSK3ß.

Nectin-4 is a breast cancer stem cell marker that induces WNT/ß-catenin signaling via Pi3k/Akt axis.

Nectin-4 is well known as a junction protein. Recent reports have implicated it in cancer, but there has been little exploration of its functional significance in metastasis and cancer stem cells. Here, using the breast cancer metastasis model system, we report Nectin-4 is a marker for breast cancer stem cells (BCSCs) and provide experimental evidence suggesting that it utilizes WNT/ß-Catenin signaling via Pi3k/Akt axis for self renewal of BCSCs. In vitro, in vivo, ex vivo and clinical pathological data showed upregulated Nectin-4 in breast cancer metastasis and WNT/ß-Catenin signaling. Nectin-4 depletion inhibited EMT, metastasis, invasion, and the WNT/ß-Catenin pathway; conversely, Nectin-4 overexpression in null cells upregulated EMT and metastasis and also induced WNT/ß-Catenin signaling via Pi3k/Akt axis, which in turn, controls cancer stem cell proliferation. Induced Nectin-4 was observed in breast tumor patient samples and in breast tumor metastases to axillary lymph nodes, which indicated that Nectin-4 is not only a BCSC marker but also a breast cancer metastasis marker. The current study provides clear evidence that Nectin-4 is a BCSC marker and is responsible for breast cancer metastasis.

Quinacrine induces apoptosis in cancer cells by forming a functional bridge between TRAIL-DR5 complex and modulating the mitochondrial intrinsic cascade.

Death Receptor 5 (DR5) is known to be an important anti-cancer drug target. TRAIL is a natural ligand of DR5, but its drug action is limited because of several factors. A few agonistic ligands were identified as TRAIL-DR5 axis modulators, which enhance the cellular apoptosis. Literature suggest that quinacrine (QC) acts as a DR5 agonistic ligand. However, the detailed mechanism explaining how QC interacts with TRAIL-DR5 axis has not been established. Also focused in vitro and in vivo experimental analysis to validate the hypothesis is not yet performed. In this work, extensive studies have been carried out using in silico analysis (molecular dynamics), in vitro analysis (cell based assays) and in vivo analysis (based on mice xenograft model), to delineate the mechanism of QC action in modulating the TRAIL-DR5 signaling. The MD simulations helped in identifying the important residues contributing to the formation of a QC-TRAIL-DR5 complex, which provide extra stability to it, consequently leading to the enhanced cellular apoptosis. QC caused a dose dependent increase of DR5 expression in cancer cells but not in normal breast epithelial cells, MCF-10A. QC showed a synergistic effect with TRAIL in causing cancer cell apoptosis. In DR5-KD MCF-10A-Tr (DR5 knocked down) cells, TRAIL+ QC failed to significantly increase the apoptosis but over expression of full length DR5 in DR5-silence cells induced apoptosis, further supporting DR5 as a drug target for QC. An increase in the release of reactive species (ROS and RNS) and activation of enzymes (FADD, CASPASES 3, 8, 9 and cytochrome-C) indicated the involvement of mitochondrial intrinsic pathway in TRAIL+QC mediated apoptosis. In vivo study pointed out that TRAIL+QC co-administration increases the expression of DR5 and reduce the tumor size in xenograft mice. This combined in silico, in vitro and in vivo analysis revealed that QC enhances the cellular apoptosis via the modulation of TRAIL-DR5 complexation and the mitochondrial intrinsic pathway.

Scaffold-Hopping of Aurones: 2-Arylideneimidazo[1,2-a]pyridinones as Topoisomerase IIα-Inhibiting Anticancer Agents.

Scaffold-hopping of bioactive natural product aurones has been studied for the first time. 2-Arylideneimidazo[1,2-a]pyridinones as potential topoisomerase IIα (hTopoIIα)-targeting anticancer compounds were considered. A multifunctional activator, polyphosphoric acid, enabled to realize a cascade reaction of 2-aminopyridine with 2,3-epoxyesters toward synthesis of 2-arylideneimidazo[1,2-a]pyridinones. Most of the compounds exhibited hTopoIIα-selective poison activity with efficiency more than etoposide and DNA-binding property, while not interacting with hTopo I. The compounds showed pronounced antiproliferative activities in nanomolar range with relatively poor toxicity to normal cells, inhibition of invasiveness, and apoptotic effect. The activities for inhibition of tubulin assembly, CDK1 and pCDK1, were also observed. Interestingly, the hTopoIIα inhibitory (in vitro and ex vivo studies) and antiproliferative activities of representative potent compounds were found to be manifold higher compared to corresponding parent aurones bearing alike substitutions, indicating the importance of such scaffold-hopping strategy in medicinal chemistry research.

SURVIVIN as a marker for quiescent-breast cancer stem cells-An intermediate, adherent, pre-requisite phase of breast cancer metastasis.

Cancer stem cells drive the metastatic cascade by undergoing epithelial to mesenchymal transition (EMT) and again mesenchymal to epithelial transition (MET). Using multiple breast cancer cell lines including cigarette smoke induced breast cancer cells and tumor derived primary cells from patient sample; we developed a breast cancer metastasis model and reported the existence of an adherent, distinct pre-metastatic phase, quiescent-breast cancer stem cells (Q-BCSCs) prior to attaining an EMT. SURVIVIN was found to be expressed in Q-BCSCs. Time dependant biphasic expression of SURVIVIN in Q-BCSCs reveals that Q-BCSCs is a pre-metastatic phase distinct from both epithelial and mesenchymal counterparts. SURVIVIN favours metastasis and up-regulates WNT/ß-CATENIN pathway in a PI3 K/AKT-dependant manner for self-renewal. Knockdown of SURVIVIN in Q-BCSCs lost the metastatic property of cells by inhibiting invasion, EMT-MET, PI3 K/AKT/WNT cascade, and induced apoptosis. Thus, our data suggest the existence of a novel pre-metastatic phase (Q-BCSCs) before EMT and SURVIVIN acts as a marker for Quiescent-BCSCs.

ABT-888 and quinacrine induced apoptosis in metastatic breast cancer stem cells by inhibiting base excision repair via adenomatous polyposis coli.

PARP inhibitors in combination with other agents are in clinical trial against cancer, but its effect on cancer stem cells (CSCs) is limited. CSCs are responsible for drug resistance, metastasis and cancer relapse due to high DNA repair capacity. Here, we present preclinical effects of Quinacrine (QC) with ABT-888, a PARP inhibitor, on highly metastatic breast cancer stem cells (mBCSCs). An increased level of Adenomatous polyposis coli (APC) was noted after treatment with ABT-888 in QC pre-treated mBCSCs cells. Increased APC physically interacts with PARP-1 and inhibits PARylation causing the non assembly of base excision repair (BER) multiprotein complex, resulting in an irreparable DNA damage and subsequent apoptosis. Knockdown of APC in mBCSCs inhibited DNA damage, increased BER and PARylation, reduces apoptosis while the over-expression of APC in BT20 (APC low expressing) cells reversed the effect. Thus, combination of QC and ABT-888 decreased mBCSCs growth by activating APC and inhibiting BER within the cells.

Chk1 inhibitor synergizes quinacrine mediated apoptosis in breast cancer cells by compromising the base excision repair cascade.

Quinacrine (QC) causes apoptosis in breast cancer cells by induction of DNA damage, arrest of cells in S-phase, and by topoisomerase inhibition. Here, we show that QC-mediated apoptosis is not only due to increased DNA damage but also by compromising cell cycle checkpoints and base excision repair (BER) capacity in breast cancer cells. QC decreased CHK1, CDKs (CDC2, MDM2, CDC6), cyclins (B1, E1) and CDC25-A in a dose dependent manner. The expression of basal ATR remains unaltered but pATR (Ser-428) increased after QC treatment. A CHK1 inhibitor, SB218078, was also tested alone and in combination with QC. Like QC, SB218078 caused apoptosis by DNA damage and S-phase arrest. The combination of QC and SB218078 increased apoptosis by blocking the cell cycle in G2/M, which caused a mitotic catastrophe, and induced DNA damage at a higher level in comparison to individual compound treatments. Both drugs individually or in combination decreased the levels of replication protein A (RPA). Measurement of the expression of BER (SP- and LP-BER) proteins and direct in vivo BER activity revealed that the QC/SB218078 combination caused apoptosis in cancer cells by disrupting the induction of BER, which represents a novel means of potentially treating breast cancer.

Anti-malarials are anti-cancers and vice versa - one arrow two sparrows.

Repurposing is the novel means of drug discovery in modern science due to its affordability, safety and availability. Here, we systematically discussed the efficacy and mode of action of multiple bioactive, synthetic compounds and their potential derivatives which are used to treat/prevent malaria and cancer. We have also discussed the detailed molecular pathway involved in anti-cancer potentiality of an anti-malarial drug and vice versa. Although the causative agents, pathophysiology and manifestation of both the diseases are different but special emphasis has been given on similar pathways governing disease manifestation and the drugs which act through deregulating those pathways. Finally, a future direction has been speculated to combat these two diseases by a single agent developed using nanotechnology. Extended combination and new formulation of existing drugs for one disease may lead to the discovery of drug for other diseases like an arrow for two sparrows.

The bioactive and therapeutic potential of Hemidesmus indicus R. Br. (Indian Sarsaparilla) root.

The root of Hemidesmus indicus R. Br., commonly known as Indian Sarsaparilla, is used traditionally to treat a wide variety of illnesses including rheumatism, leprosy, impotence, urinary tract and skin infections. The anticancer, antioxidant, anti-inflammatory, antipyretic, analgesic, antimicrobial, antidiabetic, hepatoprotective, cardioprotective, renoprotective, neuroprotective and immunomodulatory properties of H. indicus have been investigated in numerous in vivo and in vitro studies. Among these, the antioxidant and antimicrobial activity was well documented. This review details the phytochemistry and therapeutic applications of H. indicus root.