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Anti-cancer agents in medicinal chemistry [journal]
- Dinuclear Berenil-Platinum (II) Complexes as Modulators of Apoptosis in Human MCF-7 and MDA-MB231 Breast Cancer Cells. [JOURNAL ARTICLE]
- Anticancer Agents Med Chem 2014 Jun 23.
The metabolism of alkylating agents is accompanied by the generation of reactive oxygen species. The aim of this study was to treat estrogen receptor-positive and estrogen receptor-negative human breast cancer cells, MCF-7 and MDA-MB-231, respectively, with cisplatin and five different berenil-platinum (II) complexes, and then to investigate the oxidative modifications of DNA, lipid and protein, and to compare them with the profile of various pro- and antiapoptotic proteins. Changes in the levels of 8-hydroxy-2'-deoxyguanosine, 4-hydroxynonenal, carbonyl groups, dityrosine, active caspases 3, 8 and 9, as well as the expression of Bcl-2, Bax, cytochrome c, and p53 were subsequently examined. Activities of superoxide dismutase, catalase and glutathione, vitamin C levels were also investigated. Cellular reactions to cisplatin and the berenil-platinum (II) derivatives were more pronounced in MCF-7 cells as compared with the MDA-MB231 cells. Furthermore, the berenil-platinum (II) derivatives were found to be more effective than cisplatin. All of the complexes reduced the activity of superoxide dismutase and catalase, and also lowered the levels of non-enzymatic antioxidants. Increased level of lipid, protein as well as DNA damage markers was also observed after berenil-platinum (II) derivatives treatment. Similarly, the increase in the levels of the proapoptotic factors, were detected in MCF-7 and MDA-MB231 cells. Incubation of examined cells with the berenil-platinum (II) complexes also led to the increase in the levels of active caspases 3, 8 and 9. In conclusion, the results of the present study demonstrated that berenil-platinum (II) complexes more efficiently mediate cellular oxidative modifications and proapoptotic metabolism, particularly in MCF-7 cells, compared to cisplatin. Pt2(isopropylamine)4berenil2 and Pt2(piperidine)4(berenil)2 notably affected the cellular metabolism of estrogen-positive breast cancer cells. Thus, these complexes may be valuable for the design of additional anticancer drugs.
- Differential Role of Apoptosis and Autophagy Associated with Anticancer Effect of Lupulone (Hop B-Acid) Derivatives on Prostate Cancer Cells. [JOURNAL ARTICLE]
- Anticancer Agents Med Chem 2014 Jun 23.
Lupulone, a β-acid derived from hop extracts has been shown to exhibit cytotoxic activity against cancer cells. In this study we investigated the functional role of different modes of cell death that mediate anticancer effect of lupulone derivatives in prostate cancer cells. ELISA, immunoblotting and siRNA approaches were utilised to study cell death, expression of proteins of interest and their functional activities. We found that the anticancer effect of lupulone derivatives on prostate cancer cells is associated with induction of apoptosis and autophagy as determined by increases of DNA fragmentation and LC3I/ LC3II conversion respectively. Inhibition of apoptosis using a pan-caspase inhibitor resulted in increased levels of autophagy. Following screening of proteins associated with autophagy we found that Atg4β expression was increased in prostate cancer cells after treatment with lupulone. Transfection of cells with siRNA against Atg4β resulted in increased levels of apoptosis in prostate cancer cells. Treatment of prostate cancer cells with lupulone derivatives initiated two modes of cell death: apoptosis as a killing pathway and autophagy as a protection against cell death. Further studies are required to investigate the regulation of Atg4β activity in lupulone derivatives-induced a negative crosstalk between apoptosis and autophagy.
- A steroidal Na+/K+ ATPase Inhibitor Triggers Pro-Apoptotic Signaling and Induces Apoptosis in Prostate and Lung Tumor Cells. [JOURNAL ARTICLE]
- Anticancer Agents Med Chem 2014 Jun 18.
Recently we have reported potent anti-cancer actions of various steroidal Na+/K+ ATPase inhibitors in multiple cell lines. Furthermore, the most powerful compound identified in this study, the 3-[(R)-3-pyrrolidinyl]oxime derivative (3-R-POD), was highly effective in various tumor cell lines in vitro, and exhibited significant tumor growth inhibition in prostate and lung xenografts in vivo. In the present study we have addressed the molecular mechanisms implicated in the anti-cancer actions of 3-R-POD. We report here that 3-R-POD induces strong apoptotic responses in A549 lung- and in DU145 prostate- cancer cells. These effects are accompanied by significant upregulation of caspase-3 activity. Focussing on A549 cells, we further demonstrate late downregulation of BCL-2- and upregulation of c-Fos- gene transcription. In addition, the steroidal Na+/K+ ATPase inhibitor induced late dephosphorylation of Focal Adhesion Kinase (FAK) and activation of p38 MAPK. Our findings suggest that the steroidal Na+/K+ ATPase inhibitor 3-R-POD induces apoptosis, paralleled by altered BCL-2 and c-Fos gene transcription, inhibition of the pro-survival FAK signalling, upregulation of the pro-apoptotic p38 MAPK pathway and stimulation of caspase-3 activity.
- Mesenchymal Stromal Cells Uptake And Release Paclitaxel Without Reducing Its Anticancer Activity. [JOURNAL ARTICLE]
- Anticancer Agents Med Chem 2014 Jun 18.
To improve the drug delivery efficiency on target cells many strategies have been developed including also Mesenchymal Stromal Cells (MSCs) approaches. In a previous study, we found that bone-marrow-derived MSCs (BM-MSCs) were able to incorporate and release the anti-tumor and anti-angiogenic drug Paclitaxel (PTX). In this study, we evaluated the stability of PTX in standard cell culture conditions by analysing the metabolites produced by MSCs after their incorporation of the drug. We are able to show that MSCs do not release neither 3-OH-PTX nor 6-OH-PTX metabolites (having a lower anticancer activity) but the release of an active PTX molecule together with the isomer 7-Epitaxol, known to maintain the whole biological activity. This confirms that the simple procedure of MSCs priming with a drug (without any genetic cell manipulation), in our case PTX, does not modify the activity of the molecule and provide a new biological-device to carry and delivery PTX in tumor sites, by contributing to improve drug efficacy and target selectivity in cancer therapy.
- Modulation of Doxorubicin Mediated Growth Inhibition of Hepatocellular Carcinoma Cells by Platelet Lysates. [JOURNAL ARTICLE]
- Anticancer Agents Med Chem 2014 Jun 4.
Purpose. Platelet extracts can stimulate cell growth and contribute to tumor biology. It was recently shown that they stimulate the growth of hepatocellular carcinoma (HCC) cells and decrease apoptosis. Doxorubicin is a commonly used HCC chemotherapy that increases apoptosis. We therefore examined the effects of platelet lysates (hPL) on doxorubicin-mediated HCC cell growth inhibition and apoptosis induction. Methods. Three human HCC cell lines, PLC/PRF/5, Hep3B and HepG2 cells, were grown in culture and growth was measured by the MTT assay and apoptosis was measured using Muse Annexin V assay kit. Cells were also probed by Western blot. Results. hPL decreased doxorubicin-mediated growth inhibition and apoptosis induction in all three cell lines. When doxorubicin and hPL were added at separate time intervals, protection by hPL was also observed. WB showed that hPL caused prolonged and increased levels of phospho-JNK and phospho-p38. Furthermore, a p38 inhibitor abrogated the modulating effects of hPL on both growth and apoptosis, indicating its importance in mediating hPL actions. WBs also showed that hPL decreased doxorubicin-induced markers of apoptosis. Conclusions. hPL modulate the actions of the cancer chemotherapeutic agent, doxorubicin. Platelets are part of the complex microenvironmental milieu and their effects may contribute to a modulation of chemotherapy actions. Conversely, drugs that alter platelet levels or degranulation could potentially augment doxorubicin actions on HCC cells.
- Editorial: phytochemicals, intracellular signalling pathways and anti-cancer effects. [Journal Article]
- Anticancer Agents Med Chem 2014; 14(6):777-8.
- Activation of Integrin β1 Mediates the Increased Malignant Potential of Ovarian Cancer Cells Exerted by Inflammatory Cytokines. [JOURNAL ARTICLE]
- Anticancer Agents Med Chem 2014 Jun 13.
Epithelial ovarian cancer (EOC) is a highly lethal gynecological malignancy since it could not be discovered until a late stage. Identifying the molecular phenotype alteration during the development and progression of ovarian cancer is an urgent demand for the targeted intervention therapy. Recently, inflammation and Integrin beta 1(ITGB1), a subunit of heterodimeric transmembrane receptors family, had been pointed out to be involved in promoting ovarian tumorigenesis and cancer progression respectively. However, the relationship between ITGB1 and the inflammatory mediators in ovarian cancer progression remain obscure. In the present study, ITGB1 was observed to be frequently upregulated in ovarian cancer, overexpression of ITGB1 leaded to a more invasive and mesenchymal phenotype. Furthermore, our results also provided evidence concerning the role of inflammatory cytokines (IL-6, TGF-β1 and SDF-1) in ITGB1 expression as well as in the malignant potential of ovarian cancer cells. Consistently, sh-RNA mediated knocking down of ITGB1 evidently reduce tumor growth and peritoneal dissemination in in vivo Nod-scid SKOV3 orthotopic xenograft mice. Overall, the present data suggested that ITGB1 upregulation was involved in the regulation of tumorigenesis and disease exacerbation exerted by inflammatory cytokines as IL-6, TGF-β1 and SDF-1, and suggested that targeting ITGB1 and the underlying inflammatory modulator was an attractive strategy for therapeutic intervention during ovarian carcinogenesis.
- Paris polyphylla: Chemical and Biological Prospectives. [JOURNAL ARTICLE]
- Anticancer Agents Med Chem 2014 Jun 10.
Paris polyphylla J.E. Smith is extensively used in traditional systems of Indian and Chinese medicine mainly for its anticancerous property. The national and international demand for P. polyphylla is constantly increasing and most of the supply comes from wild. Illegal and unscientific exploitation coupled with habitat destruction decreases the natural population of the herb, as a consequence this species comes under vulnerable category. Restoration and conservation of the natural population of this potential herb is prerequisites. This article aims to provide an overview on chemical and biological prospective of P. polyphylla. Secondary metabolites such as daucosterol, polyphyllin D, β-ecdysterone, Paris saponins I, II, V, VI, VII, H, dioscin, oligosaccharides, heptasaccharide, octasaccharide, trigofoenoside A, protogracillin, Paris yunnanosides G-J, padelaoside B, pinnatasterone, formosanin C and 20-hydroxyecdyson saponins have been isolated form P. polyphylla. Several biological activities such as anticancerous, antitumor, cytotoxic, anthelmintic, antimicrobial, antiangiogenic, immunostimulating, contractile and hemostatic have also been reported. Consequently, this review will be helpful to the researcher and scientist for further research.
- Novel action and Mechanism of Auranofin in Inhibition of Vascular Endothelial Growth Factor Receptor-3-Dependent Lymphangiogenesis. [JOURNAL ARTICLE]
- Anticancer Agents Med Chem 2014 Jun 9.
Auranofin is a gold compound initially developed for the treatment of rheumatoid arthritis. Recent data suggest that auranofin has promise in the treatment of other inflammatory and proliferative diseases. However, the mechanisms of action of auranofin have not been well defined. In the present study, we identify vascular endothelial growth factor receptor-3 (VEGFR3), an endothelial cell (EC) surface receptor essential for angiogiogenesis and lymphangiogenesis, as a novel target of auranofin. In both primary EC and EC cell lines, auranofin induces downregulation of VEGFR3 in a dose-dependent manner. Auranofin at high doses (≥1 M) decreases cellular survival protein thioredoxin reductase (TrxR2), TrxR2-dependent Trx2 and transcription factor NF-B whereas increases stress signaling p38MAPK, leading to EC apoptosis. However, auranofin at low doses (≤0.5 M) specifically induces downregulation of VEGFR3 and VEGFR3-mediated EC proliferation and migration, two critical steps required for in vivo lymphangiogenesis. Mechanistically, we show that auranofin-induced VEGFR3 downregulation is blocked by antioxidant N-acetyl-L-cysteine (NAC) and lysosome inhibitor chloroquine, but was promoted by proteasomal inhibitor MG132. These results suggest that auranofin induces VEGFR3 degradation through a lysosome-dependent pathway. Auranofin may be a potent therapeutic agent for the treatment of lymphangiogenesis-dependent diseases such as lymphedema and cancer metastasis.
- Deoxypodophyllotoxin Isolated from Juniperus Communis Induces Apoptosis in Breast Cancer Cells. [JOURNAL ARTICLE]
- Anticancer Agents Med Chem 2014 Jun 8.
The study of anticancer properties from natural products has regained popularity as natural molecules provide a high diversity of chemical structures with specific biological and medicinal activity. Based on a documented library of the most common medicinal plants used by the indigenous people of North America, we screened and isolated compounds with anti-breast cancer properties from the Juniperus communis (common juniper) species. Using bioassay-guided fractionation of a crude plant extract, we identified the diterpene isocupressic acid and the aryltetralin lignan deoxypodophyllotoxin (DPT) as potent inducers of caspase-dependent programmed cell death (apoptosis) in malignant MB231 breast cancer cells. Further elucidation revealed that DPT, in contrast to isocupressic acid, also concomitantly inhibited cell survival pathways mediated by the MAPK/ERK and NF B signaling pathways within hours of treatment. Our findings emphasize the potential and importance of natural product screening for new chemical entities with novel anticancer activities. Natural products research complemented with the wealth of information available through the ethnobotanical and ethnopharmacological knowledge of the indigenous peoples of North America can provide new candidate entities with desirable bioactivities to develop new cancer therapies.