Glucocorticoid receptor: a harmonizer of cellular plasticity in breast cancer-directs the road towards therapy resistance, metastatic progression and recurrence.

Recent therapeutic advances have significantly uplifted the quality of life in breast cancer patients, yet several impediments block the road to disease-free survival. This involves unresponsiveness towards administered therapy, epithelial to mesenchymal transition, and metastatic progression with the eventual appearance of recurrent disease. Attainment of such characteristics is a huge adaptive challenge to which tumour cells respond by acquiring diverse phenotypically plastic states. Several signalling networks and mediators are involved in such a process. Glucocorticoid receptor being a mediator of stress response imparts prognostic significance in the context of breast carcinoma. Involvement of the glucocorticoid receptor in the signalling cascade of breast cancer phenotypic plasticity needs further elucidation. This review attempted to shed light on the inter-regulatory interactions of the glucocorticoid receptor with the mediators of the plasticity program in breast cancer; which may provide a hint for strategizing therapeutics against the glucocorticoid/glucocorticoid receptor axis so as to modulate phenotypic plasticity in breast carcinoma.

Isolation, Cytotoxicity, and In-silico Screening of Coumarins from Psoralea corylifolia Linn.

Psoralea corylifolia (syn. Cullen corylifolium), commonly called bawachi, is a medicinal plant extensively used for skin conditions like leukoderma, vitiligo, and psoriasis. It is notably rich in valuable bioactive compounds, particularly coumarins and furanocoumarins. This study isolated fourteen coumarins from P. corylifolia which were tested for cytotoxicity using the MTT assay, with compound 10 showing good cytotoxicity against A549 cells (IC50 0.9 µM), while compound 1, compound 2, and compound 3 displaying potential cytotoxicity against MDA-MB-231 cells (IC50 0.49 µM, 0.56 µM, and 0.84 µM respectively). Additionally, the compounds' interaction with Epidermal Growth Factor Receptor (EGFR) protein, highly expressed in both cell lines, was investigated through molecular modeling studies, that aligned well with cytotoxicity results. The findings revealed the remarkable cytotoxic potential of four coumarins 1, 2, 3, and 10 against A549 and MDA-MB-231 cell lines.

In silico analysis, isolation, and cytotoxicity evaluation of the coumestans from Cullen corylifolium (L.) Medik.

Cullen corylifolium is well known for diverse phytoconstituents that possess multifaceted pharmacology, and one such less explored class is coumestans, which have not been well explored for their anticancer activities. One of the popular cancer targets is the Epidermal Growth Factor Receptor, a tyrosine kinase involved in various cancers, especially breast and lung cancer hence, a crucial cancer target. This work is focussed on molecular docking and molecular simulation studies on coumestans against EGFR. The rigorous docking studies resulted in two coumestans (1 and 5) with binding energy less than Gefitinib and Erlotinib. Compounds 1 and 5 were subjected to molecular simulation, binding free energy calculation, per-residue energy decomposition, and in silico ADMET prediction. The best hit, compound 1 was evaluated for its cytotoxicity against MDA-MB-231 and A549 cells via in vitro assay. The ligand-protein complex exhibited good stability, binding free energies, better in silico pharmacokinetics, low toxicity, and good cytotoxicity.

Sulphoraphane, a naturally occurring isothiocyanate induces apoptosis in breast cancer cells by targeting heat shock proteins.

Heat shock proteins (HSPs) are involved in protein folding, aggregation, transport and/or stabilization by acting as a molecular chaperone, leading to inhibition of apoptosis by both caspase dependent and/or independent pathways. HSPs are overexpressed in a wide range of human cancers and are implicated in tumor cell proliferation, differentiation, invasion and metastasis. HSPs particularly 27, 70, 90 and the transcription factor heat shock factor1 (HSF1) play key roles in the etiology of breast cancer and can be considered as potential therapeutic target. The present study was designed to investigate the role of sulphoraphane, a natural isothiocyanate on HSPs (27, 70, 90) and HSF1 in two different breast cancer cell lines MCF-7 and MDA-MB-231 cells expressing wild type and mutated p53 respectively, vis-à-vis in normal breast epithelial cell line MCF-12F. It was furthermore investigated whether modulation of HSPs and HSF1 could induce apoptosis in these cells by altering the expressions of p53, p21 and some apoptotic proteins like Bcl-2, Bax, Bid, Bad, Apaf-1 and AIF. Sulphoraphane was found to down-regulate the expressions of HSP70, 90 and HSF1, though the effect on HSP27 was not pronounced. Consequences of HSP inhibition was upregulation of p21 irrespective of p53 status. Bax, Bad, Apaf-1, AIF were upregulated followed by down-regulation of Bcl-2 and this effect was prominent in MCF-7 than in MDA-MB-231. However, very little change in the expression of Bid was observed. Alteration in Bcl-2 Bax ratio resulted in the release of cytochrome c from mitochondria and activation of caspases 3 and 9 which are in agreement with apoptotic index values. Sulphoraphane therefore can be regarded as a potent inducer of apoptosis due to HSP modulation in breast cancer cells.

Placental Thickness Measurement by Ultrasonography and Its Correlation with Gestational Age of Fetus in the Manipuri Population.

Purpose: The study was done to measure the placental thickness (PT) in pregnant women and find its correlation with the gestational age (GA) of the fetus by ultrasonography. Comparisons were also made with the other fetal biometry parameters, and baseline data were generated with respect to the gestational weeks and placental position. Materials and Methods: The study was a cross-sectional one with a sample size of 134 singleton pregnancies. About 11-40 weeks of gestation were studied for the measurement of PT and other fetal parameters. Informed consent was obtained before recording the data on the preformed questionnaire. All measurements were done in mm and during the relaxed phase of the uterus. Results: As per the study, PT (in mm) increases with an increase in GA (in weeks) and almost matches it from 12 to 34 weeks of gestation. PT had a strong correlation with GA (r = 0.966). The correlation was statistically significant, with a P < 0.001. Conclusion: Thus, the estimation of the thickness of the placenta at the cord insertion site by means of ultrasonography is a relatively simple, safe, and cheap modality for accurate estimation of GA, fetal growth, and placental abnormalities and thus can significantly affect the management and outcome of pregnancy.

Total Synthesis and Stereochemical Assignment of Sunshinamide and Its Anticancer Activity.

Total synthesis of cyclodepsipeptide sunshinamide has been achieved for the first time using a convergent approach. The key features of this synthesis comprise Crimmins acetate aldol, Shiina esterification, amide coupling, macrolactamization, and an I2-mediated deprotection with concomitant disulfide-bridge formation. This synthetic study enabled the unambiguous determination of the stereochemistry of the unassigned stereocenter of the isolated sunshinamide. The cytotoxicity of sunshinamide and one of its analogues was evaluated against different cancerous and noncancerous human cell lines, which revealed their attractive and selective activities toward cancer cells at very low concentrations.

Curcumin ameliorates the targeted delivery of methotrexate intercalated montmorillonite clay to cancer cells.

Montmorillonite Clay (MMT) is aimed to develop as an orally administrable drug delivery vehicle with enhanced efficacy. Aiming to enhance the therapeutic index of methotrexate, curcumin is concomitantly used with methotrexate in the present study. Being folate antagonist in nature, methotrexate is internalized into cells by folate receptor (FR); which is over-expressed in certain human cancer cells such as cervical carcinoma cells (HeLa). Firstly, montmorillonite Clay (MMT) is organically modified (OMMT) with cetyl trimethyl ammonium bromide (CTAB) and used to intercalate curcumin and methotrexate separately, designated as OMMT-Cur and OMMT-MTX, respectively. XRD pattern demonstrated successful intercalation of therapeutics and an increase in clay interlayer distance facilitated by CTAB. The dissolution kinetics of methotrexate follows Higuchi model for both Simulated Gastric Fluid (SGF) and Simulated Intestinal Fluid (SIF), while the release kinetics for curcumin fitted into Higuchi model for SGF and Hixson-Crowell model for SIF, respectively. OMMT-MTX are able to discriminate FR-positive HeLa cells from FR-negative breast cancer cells (MCF7); irrespective of alike cellular phenotypes. Further, the pre-treatment of HeLa cells with curcumin improves its sensitivity towards methotrexate causing a greater killing of the Hela cells. Together, the results propose the concomitant use of curcumin and methotrexate for successfully targeting highly invasive FR-positive carcinomas by means of folate receptor using MMTs.

Phenethyl isothiocyanate, by virtue of its antioxidant activity, inhibits invasiveness and metastatic potential of breast cancer cells: HIF-1α as a putative target.

Hypoxia-inducible factor 1α (HIF-1α) plays a crucial role in facilitating tumor progression and metastasis. Reducing the levels of HIF-1α might therefore be an important anticancer strategy. This could be achieved by understanding the key cellular events involved in HIF-1α activation. Present study explored the effect of phenethyl isothiocyanate (PEITC), a natural isothiocyanate, found in cruciferous vegetables on the expression of HIF-1α and HSP90 in breast adenocarcinoma cell lines (MCF-7 and MDA-MB-231) under both normoxia and hypoxia. This study established the possible role of ROS in the up-regulation of these markers in breast cancer cells. PEITC-induced nuclear accumulation of Nrf2, increased the activities of several antioxidant enzymes, and thus reduced the ROS burden of the tumor cells by acting as an indirect antioxidant. This resulted in the down-regulation of HSP90 and thereby HIF-1α expression. HSP90 was also found to be involved in the regulation of HIF-1α. A probable link between down-regulation of HIF-1α with reduction of ROS by PEITC through induction of Nrf2 was determined. Finally, our study demonstrated that modulation of HIF-1α by PEITC retarded adhesion, aggregation, migration and invasion of the breast cancer cells, thereby showing anti-metastatic effect. Activities of MMPs (2 & 9) and expression of VEGF were also altered by PEITC.

Inhibition of crosstalk between Bcr-Abl and PKC signaling by PEITC, augments imatinib sensitivity in chronic myelogenous leukemia cells.

Chronic myelogenous leukemia (CML), a clonal hyperproliferation of immature blood cells accounts for 20% of adult leukemia cases. Reciprocal translocation of chromosomes 9 and 22, results into Bcr-Abl fusion and is responsible for expression of a tyrosine kinase protein p210(bcr/abl), which mediates several survival pathways and confer therapeutic resistance. Protein kinase C (PKC), a family of serine threonine kinases play an important role in the process of leukemogenesis. A crosstalk between Bcr-Abl and PKC signaling has been documented. Therefore, targeting p210(bcr/abl) and its associated signaling proteins using non-toxic natural means will be an effective strategy for antileukemic therapy. Aim of the present study is to investigate whether PEITC, a natural isothiocyanate in combination with imatinib mesylate (IM), a tyrosine kinase inhibitor could increase the therapeutic efficacy of IM by modulating the expression of p210(bcr/abl). Enhanced cytotoxic efficacy of IM by PEITC was further validated using another myelogenous leukemia cell line, KU812. It was observed that PEITC in combination with IM efficiently downregulated the expression of p210(bcr/abl) in chronic myelogenous leukemia cell lines (K-562). PEITC inhibited the expressions of PKCα, PKCßII and PKCζ (both phosphorylated and total form). Expression of Raf1 and ERK1/2, two important target proteins in PKC signaling cascade was diminished. The result indicated that PEITC ultimately reduced expression of Raf1 and ERK1/2 through Bcr-Abl and PKC inhibition. This result was further confirmed by UCN-01, a selective PKC inhibitor and IM; indicating an association between p210(bcr/abl) and PKC with Raf1 and ERK1/2. PEITC thus may have enormous potential in synergistic therapy of leukemia by enhancing drug efficacy.

In search of natural remediation for cervical cancer.

Cancer is a serious global health issue. Cancer of the cervix is one of the leading gynecological malignancies worldwide; though it is more prevalent in the developing countries. Fruitful approaches are needed to control cervical cancer. Awareness through proper education, screening and early detection may pave a way to combat the disease process in the first place. Surgery, chemotherapy and radiotherapy are some of the common modes of treatment for cervical cancer. Conventional medical treatments often are not able to eliminate the offending growth fully and are not free from complications. Side effects very often are disastrous. Therefore, it is high time to focus our attention to bring about a novel way to tackle the problem. Advocating holistic approach using plant derived phytochemicals may address this health problem. These molecules show potent anticancer potential and are free from toxicity. Adjunctive therapies using phytochemicals may prove to be of tremendous importance. Plants are a prime source of effective drugs for the treatment of various forms of cancer. Many of these compounds are well characterized and have led the researchers to develop potential chemotherapeutic agents. Neutraceuticals may not replace the conventional treatment regimen, but they may enhance the efficacy of chemotherapy and radiotherapy.

Curcumin augments the efficacy of antitumor drugs used in leukemia by modulation of heat shock proteins via HDAC6.

Heat shock proteins (HSPs) and histone deacetylase 6 (HDAC6) are induced under oxidative stress, which promotes oncogenesis. HSPs are regulated by heat shock factor1 (HSF1). HDAC6, a class IIb deacetylase, plays an essential role in tumorigenesis and cell stress response. HSPs, HSF1 and HDAC6 are up-regulated in cancer. In the present study, we explored the effect of curcumin, a phytochemical, on HSPs (27, 70, 90), HSF1 and HDAC6 in two different leukemia cell lines (K-562 and HL-60). The association between HDAC6, HSPs, and intrinsic oxidative stress was also investigated. Overexpression of HSPs (27, 70, 90), HSF1, and HDAC6 in leukemia cells were down-regulated by curcumin, and the effects on HSPs 27and 70 were less than that on HSP 90. This resulted in cell cycle arrest at the G2/M stage, leading to apoptosis. Different cell cycle regulatory proteins (p53, p21, cyclin B1, CDK1, Cdc25C) and some apoptosis-related proteins (Bcl-2, Bax, Bid, Bad, Apaf1, AIF and Cyt c) were altered by curcumin. Increased ROS levels in leukemia cells were quenched by curcumin. A probable association between high ROS level and the overexpression of the tumor markers was established in this study. Thus, curcumin enhanced the efficacy of anti-tumor drugs imatinib-mesylate and cytarabine through the inhibition of the tumor markers.

Curcumin sensitizes chemotherapeutic drugs via modulation of PKC, telomerase, NF-kappaB and HDAC in breast cancer.

BACKGROUND: Several tumor markers are overexpressed in breast cancer. Chemotherapy in breast cancer fails due to resistance to chemotherapeutic drugs. A phytochemical such as curcumin can be used in a therapeutic modality as it elicits anti-tumor effects. METHODS: Action of curcumin on the expression of several tumor markers, such as protein kinase C, telomerase, NF-kappaB and histone deacetylase in MCF-7 (ER positive), MDA-MB-231 (ER negative), MCF- 12F (control) and also in mice mammary tumors were investigated. RESULTS: Curcumin downregulated the expression of tumor markers both in vitro and in vivo and sensitized tumor cells to the chemotherapeutic drugs cyclophosphamide and paclitaxel. DISCUSSION: Curcumin may be of considerable value in synergistic therapy of cancer such that the drug dose level could be minimized reducing the associated toxicity.