Merve Erkisa

Novel 1-(7-ethoxy-1-benzofuran-2-yl) substituted chalcone derivatives: Synthesis, characterization and anticancer activity

Cancer treatment still requires new compounds to be discovered. Chalcone and its derivatives exhibit anticancer potential in different cancer cells. A new series of benzofuran substituted chalcone derivatives was synthesized by the base-catalyzed Claisen-Schmidt reaction of the 1-(7-ethoxy-1-benzofuran-2-yl) ethanone with different aromatic aldehydes to yield 1-(7-ethoxy-1-benzofuran-2-yl) substituted chalcone derivatives 3a-j. The derivatives were characterized by elemental analysis, FT-IR, 1H NMR and 13C NMR spectroscopy techniques. The anti-growth effect of chalcone compounds was tested in breast cancer (MCF-7), non-small cell lung cancer (A549) and prostate cancer (PC-3) cell lines by the SRB and ATP cell viability assays. Apoptosis was detected by mitochondrial membrane potential, Annexin V staining and caspase 3/7 activity. Formation of reactive oxygen species was determined by DCFDA. The results revealed that chalcone derivatives have anticancer activity with especially chalcone derivative 3a showing cytotoxic effects on cancer cells. In addition, chalcone derivative 3a induced apoptosis through caspase dependent pathways in prostate, lung and breast cancer cells.

Enhanced cytotoxic activity of doxorubicin through the inhibition of autophagy in triple negative breast cancer cell line

BACKGROUND The outcome of triple negative breast cancer is still poor and requires improvement with better therapy options. Autophagy has recently been shown to play a role in anticancer drug resistance. Therefore, we investigated if the effectiveness of doxorubicin was augmented by the inhibition of autophagy. METHODS MDA-MB-231 was used as a model cell line for triple negative breast cancer and 3-methyladenine was used as an inhibitor of autophagy. Cells were treated with 0.46-1.84μM doxorubicin and 2.5-10μM 3-methyladenine for 48h. Cell death mode was examined with M30 and M65 ELISA assays. ROS level and LDH activity was examined and the cellular acidic compartment of cells was monitored by acridine orange staining. The expression of various autophagy and apoptosis related proteins/genes were evaluated with Western blotting and RT-qPCR respectively. RESULTS Synergism was observed between the compounds (CI value<1.0). RT-qPCR analysis revealed that the combination resulted in a down-regulation of autophagy-related genes. Moreover, the combination resulted in a different cell death modality, upregulating necroptosis-related genes. This suggests that the mode of cell death may switch from apoptosis to necroptosis, which is a more severe form of cell death, when autophagy is inhibited. These results were further confirmed at protein level by Western blotting. CONCLUSION Inhibition of autophagy seems to sensitize triple negative breast cancer cells to doxorubicin, warranting further in vivo studies for the proof of this concept. GENERAL SIGNIFICANCE Autophagy has a key role in drug resistance in MDA-MB-231 cells. Therefore combinatorial approaches may effectively overcome resistance.

A promising natural product, pristimerin, results in cytotoxicity against breast cancer stem cells in vitro and xenografts in vivo through apoptosis and an incomplete autopaghy in breast cancer

Graphical abstract Figure. No caption available. HighlightsDynamics and control of reactive distillation using an extraneous entrainer for the production of n‐butyl acetate are studied.Different multiplicities are found to appear depending on whether the azeotrope that forms with water is binary or ternary.Different control schemes depending on the type of azeotrope are proposed. &NA; Several natural products have been suggested as effective agents for the treatment of cancer. Given the important role of CSCs (Cancer Stem Cells) in cancer, which is a trendy hypothesis, it is worth investigating the effects of pristimerin on CSCs as well as on the other malignant cells (MCF‐7 and MDA‐MB‐231) of breast cancer. The anti‐growth activity of pristimerin against MCF‐7 and MCF‐7s (cancer stem cell enriched population) cells was investigated by real time viability monitorization (xCELLigence System®) and ATP assay, respectively. Mode of cell death was evaluated using electron and fluorescence microscopies, western blotting (autophagy, apoptosis and ER‐stress related markers) and flow cytometry (annexin‐V staining, caspase 3/7 activity, BCL‐2 and PI3K expressions). Pristimerin showed an anti‐growth effect on cancer cells and cancer stem cells with IC50 values ranging at 0.38–1.75 &mgr;M. It inhibited sphere formation at relatively lower doses (<1.56 &mgr;M). Apoptosis was induced in MCF‐7 and MCF‐7s cells. In addition, extensive cytoplasmic vacuolation was observed, implying an incompleted autophagy as evidenced by the increase of autophagy‐related proteins (p62 and LC3‐II) with an unfolded protein response (UPR). Pristimerin inhibited the growth of MCF‐7 and MDA‐MB‐231‐originated xenografts in NOD.CB17‐Prkdcscid/J mice. In mice, apoptosis was further confirmed by cleavage of PARP, activation of caspase 3 and/or 7 and TUNEL staining. Taken together, pristimerin shows cytotoxic activity on breast cancer both in vitro and in vivo. It seems to represent a robust promising agent for the treatment of breast cancer. Pristimerins itself or synthetic novel derivatives should be taken into consideration for novel potent anticancer agent(s).

Folic acid-conjugated cationic Ag2S quantum dots for optical imaging and selective doxorubicin delivery to HeLa cells

AIM We aim to develop folic acid (FA)-conjugated cationic Ag2S near-infrared quantum dots (NIRQDs) for the delivery of doxorubicin (DOX) selectively to folate receptor (FR)-positive cancer cells to achieve enhanced drug efficacy and optical tracking in the NIR region. MATERIALS & METHODS Cationic Ag2S NIRQDs were decorated with FA using a PEG bridge and loaded with DOX. In vitro studies were performed on FR-positive human cervical carcinoma cells and FR-negative A549 cells. RESULTS Significantly higher uptake of DOX by human cervical carcinoma cells cells and a greater therapeutic effect along with a strong intracellular optical signal were obtained with DOX-loaded FA-conjugated Ag2S NIRQDs. CONCLUSION These Ag2S NIRQDs are promising theranostic nanoparticles for receptor-mediated delivery of DOX with enhanced drug efficacy combined with optical imaging.

Synthesis, structures and anticancer potentials of platinum(II) saccharinate complexes of tertiary phosphines with phenyl and cyclohexyl groups targeting mitochondria and DNA

A series of new Pt(II) saccharinate complexes containing PR3 ligands (PPh3, PPh2Cy, PPhCy2 and PCy3) with progressive phenyl (Ph) replacement by cyclohexyl (Cy) were synthesized and structurally characterized by IR, NMR, ESI-MS and X-ray diffraction. The anticancer activity of the complexes was tested against human breast (MCF-7), lung (A549), colon (HCT116), and prostate (DU145) cancer cell lines as well as against normal bronchial epithelial (BEAS-2B) cells. Trans-configured complexes 1, 3 and 5 emerged as potential anticancer drug candidates. The mechanism of action of the potent complexes was then investigated in detail. The three complexes interacted with DNA by groove binding and with HSA via hydrophobic IIA subdomain. Furthermore, the complexes cleaved plasmid DNA efficiently. Cellular uptake studies in MCF-7 cells showed that the biologically active complexes were mainly localized in cytoplasm. The cytotoxic activity was a function of the lipophilicity and cellular accumulation of the complexes. As determined by M30, Annexin V and Caspase 3/7 activity assays, the complexes induced apoptosis in MCF-7 and HCT116 cells. Mechanistic studies showed that the potent complexes cause excessive generation of reactive oxygen species (ROS) and display a dual action, concurrently targeting both mitochondria and genomic DNA.

Pd(II) and Pt(II) saccharinate complexes of bis(diphenylphosphino)propane/butane: Synthesis, structure, antiproliferative activity and mechanism of action

[M(sac)2(dppp)] (1 and 2), [M(dppp)2](sac)2 (3 and 4) and [M(sac)2(dppb)] (5 and 6) complexes, where M = PdII (1, 3 and 5) and PtII (2, 4 and 6), sac = saccharinate, dppp = 1,3-bis(diphenylphosphino)propane and dppb = 1,4-bis(diphenylphosphino)butane, were synthesized and characterized by IR, NMR, ESI-MS and X-ray diffraction. The anticancer activity of the complexes against human lung (A549), breast (MCF-7), prostate (DU145) and colon (HCT116) cancer cell lines showed that the cationic complexes of dppp (3 and 4) and neutral Pt complex of dppb (6) were the most active agents of series. 3 and 4 exhibited antiproliferative activity, while 6 was highly cytotoxic compared to cisplatin. These complexes were therefore subjected to further investigations to ascertain the possible role of lipophilicity, cellular uptake and DNA/HSA binding in their biological activity. Flow cytometry analysis revealed that complex 6 induced apoptotic cell death in A549 and HCT116 cells and caused the cell cycle arrest at the S phase and overproduction of reactive oxygen species (ROS), giving rise to mitochondrial depolarization and DNA damage.