Biotinylated Platinum(II) Ferrocenylterpyridine Complexes for Targeted Photoinduced Cytotoxicity

Biotinylated platinum(II) ferrocenylterpyridine (Fc-tpy) complexes Pt(Fc-tpy) (L-1)] Cl (1) and Pt (Fc-tpy)(L-2)]Cl (2), where HL1 and HL2 are biotin-containing ligands, were prepared, and their targeted photoinduced cytotoxic effect in cancer cells over normal cells was studied. A nonbiotinylated complex, Pt(Fc-tpy)(L-3)]Cl (3), was prepared as a control to study the role of the biotin moiety in cellular uptake properties of the complexes. Three platinum(II) phenylterpyridine (Ph-tpy) complexes, viz., Pt(Ph-tpy)(L-1)]Cl (4), Pt(Ph-tpy)(L-2)] (5), and Pt(Ph-tpy)(L-3)]Cl (6), were synthesized and explored to understand the role of a metal-bound Fc-tpy ligand over Ph-tpy as a photoinitiator. The Fc-tpy complexes displayed an intense absorption band near 640 nm, which was absent in their Ph-tpy analogues. The Fc-tpy complexes (1 mM in 0.1 M TBAP) showed an irreversible cyclic voltammetric anodic response of the Fc/Fc(+) couple near 0.25 V. The Fc-tpy complexes displayed photodegradation in red light of 647 nm involving the formation of a ferrocenium ion (Fc(+)) and reactive oxygen species (ROS). Photoinduced release of the biotinylated ligands was observed from spectral measurements, and this possibly led to the controlled generation of an active platinum(II) species, which binds to the calf-thymus DNA used for this study. The biotinylated photoactive Fc-tpy complexes showed significant photoinduced cytotoxicity, giving a IC50 value of similar to 7 mu M in visible light of 400-700 nm with selective uptake in BT474 cancer cells over HBL-100 normal cells. Furthermore, ferrocenyl complexes resulted in light-induced ROS-mediated apoptosis, as indicated by DCFDA, annexin V/FITC staining, and sub-G1 DNA content determined by fluorescent activated cell sorting analysis. The phenyl analogues 4 and 5 were photostable, served as DNA intercalators, and demonstrated selective cytotoxicity in the cancer cells, giving IC50 values of similar to 4 mu M

JMJD6 induces HOTAIR, an oncogenic lincRNA, by physically interacting with its proximal promoter

Using microarray analysis, we found that HOX transcript antisense intergenic RNA (HOTAIR) is up-regulated by Jumonji domain containing-6 (JMJD6), a bifunctional lysyl hydroxylase and arginine demethylase. In breast cancer, both JMJD6 and HOTAIR RNAs increase tumor growth and associate with poor prognosis but no molecular relationship between them is known. We show that overexpression of JMJD6 increased HOTAIR expression and JMJD6 siRNAs suppressed it in ER+ MCF-7, triple negative MDA-MB-231 and non-breast cancer HEK 293 cells. Therefore, JMJD6 regulates HOTAIR independent of ER status. Using various deletion constructs spanning (-1874 to +50) of the HOTAIR promoter, we identified pHP216 (-216 to +50 bp) as the smallest construct that retained maximal JMJD6 responsiveness. In ChIP assays, JMJD6 bound this region suggesting that JMJD6 may be directly recruited to the HOTAIR promoter. Mutant JMJD6H187A that is devoid of enzymatic activity could bind this site but failed to induce transcription. ChIP and electromobility shift assays identified a JMJD6 interaction region from (-123 to -103 bp) within the HOTAIR promoter. In tumor samples but not normal breast tissue, the expression of JMJD6 linearly correlated with HOTAIR suggesting that JMJD6-mediated up-regulation may occur specifically in tumors. Further, concurrent high expression of both genes correlated with poor survival when individual expression of either gene showed no significant association in TCGA datasets. We propose that high JMJD6 expression may achieve higher levels of HOTAIR in breast tumors. Further, since high levels of HOTAIR promote metastasis and death, blocking JMJD6 may be useful in preventing such events

Coordination-driven self-assembly of ruthenium(II) architectures: synthesis, characterization and cytotoxicity studies

Coordination-driven self-assembly of organometallic eta(6)-arene ruthenium(ii) supramolecular architectures (MA(1)-MA(4)) was carried out by employing dinuclear ruthenium acceptors Ru-2(mu-eta(4)-C2O4)(CH3OH)(2)(eta(6)-p-cymene)(2)](CF3SO3)(2) (Ru-a), Ru-2(mu-eta(4)-C6H2O4)(CH3OH)(2)(eta(6)-p-cymene)(2)](CF3SO3)(2) (Ru-b), Ru-2(dhnq)(H2O)(2)(eta(6)-p-cymene)(2)](CF3SO3)(2) (Ru-c) and Ru-2(dhtq)(H2O)(2)((6)-p-cymene)(2)](CF3SO3)(2) (Ru-d) separately with a new tetratopic donor (TD) in methanol at room temperature TD = N,N,N,N-tetra(pyridin-4-yl)-1,1-biphenyl]-4,4-diamine]. All the coordination architectures were characterized by using spectroscopic techniques. The potency of these self-assembled architectures against human cervical cancer HeLa and human lung adenocarcinoma A549 cell lines is explored in vitro using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide), annexin V-FITC/PI and 2,7-dichlorofluorescein-diacetate assays

Self-Assembly of Discrete Ru^II₈ Molecular Cages and Their in Vitro Anticancer Activity

Four new octanudear Ru(II) cages (OC-1-OC-4) were synthesized from dinuclear p-cymene ruthenium(II) acceptors Ru-2(mu-eta(4)-C2O4)(CH3OH)(2)(eta(6)-p-cymene)(2)](O3SCF3)(2) (A(1)), Ru-2(mu-n(4)-C6H2O4)(CH3OH)(2)(eta(6)-p-cymene)(2)]-(O3SCF3)(2) (A(2)), RU2(dhnq) (H2O)(2) (eta(6)-p-cymene)(2)] (O3SCF3)(2) (A(3)), and Ru-2(dhtq)(H2O)(2)(eta(6)-p-cymene)(2)](O3SCF3)(2) (A4) separately with a tetradentate pyridyl ligand (L-1) in methanol using coordination-driven self-assembly L-1= N,N,N',N'-tetra(pyridin-4-yl)benzene-1,4-diamine]. The octanudear cages are fully characterized by various spectroscopic techniques including single-crystal X-ray diffraction analysis of OC-4. The self-assembled cages show strong in vitro anticancer activity against human lung adenocarcinoma A549 and human cervical cancer HeLa cell lines as observed from the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Of all the octanuclear cages, OC-3 exhibits remarkable anticancer activity against both cancer cell lines and is more active than that reported for cisplatin. The excellent anticancer activity of OC-3 and OC-4 highlights the importance of the synergistic effects of the spacer component of the dinuclear p-cymene Ru(11) acceptor clips

Biotinylated Platinum(II) Ferrocenylterpyridine Complexes for Targeted Photoinduced Cytotoxicity

Biotinylated platinum­(II) ferrocenylterpyridine (Fc-tpy) complexes [Pt­(Fc-tpy)­(L1)]Cl (1) and [Pt­(Fc-tpy)­(L2)]Cl (2), where HL1 and HL2 are biotin-containing ligands, were prepared, and their targeted photoinduced cytotoxic effect in cancer cells over normal cells was studied. A nonbiotinylated complex, [Pt­(Fc-tpy)­(L3)]Cl (3), was prepared as a control to study the role of the biotin moiety in cellular uptake properties of the complexes. Three platinum­(II) phenylterpyridine (Ph-tpy) complexes, viz., [Pt­(Ph-tpy)­(L1)]Cl (4), [Pt­(Ph-tpy)­(L2)]Cl (5), and [Pt­(Ph-tpy)­(L3)]Cl (6), were synthesized and explored to understand the role of a metal-bound Fc-tpy ligand over Ph-tpy as a photoinitiator. The Fc-tpy complexes displayed an intense absorption band near 640 nm, which was absent in their Ph-tpy analogues. The Fc-tpy complexes (1 mM in 0.1 M TBAP) showed an irreversible cyclic voltammetric anodic response of the Fc/Fc+ couple near 0.25 V. The Fc-tpy complexes displayed photodegradation in red light of 647 nm involving the formation of a ferrocenium ion (Fc+) and reactive oxygen species (ROS). Photoinduced release of the biotinylated ligands was observed from spectral measurements, and this possibly led to the controlled generation of an active platinum­(II) species, which binds to the calf-thymus DNA used for this study. The biotinylated photoactive Fc-tpy complexes showed significant photoinduced cytotoxicity, giving a IC50 value of ∼7 μM in visible light of 400–700 nm with selective uptake in BT474 cancer cells over HBL-100 normal cells. Furthermore, ferrocenyl complexes resulted in light-induced ROS-mediated apoptosis, as indicated by DCFDA, annexin V/FITC staining, and sub-G1 DNA content determined by fluorescent activated cell sorting analysis. The phenyl analogues 4 and 5 were photostable, served as DNA intercalators, and demonstrated selective cytotoxicity in the cancer cells, giving IC50 values of ∼4 μM

Photoactive platinum(II) beta-diketonates as dual action anticancer agents

Platinum(II) complexes, viz. Pt(L)(cur)] (1), Pt(L)(py-acac)] (2) and Pt(L)(an-acac)] (3), where HL is 4,4'-bis-dimethoxyazobenzene, Hcur is curcumin, Hpy-acac and Han-acac are pyrenyl and anthracenyl appended acetylacetone, were prepared, characterized and their anticancer activities were studied. Complex Pt(L) (acac)] (4) was used as a control. Complex 1 showed an absorption band at 430 nm (epsilon = 8.8 x 10(4) M-1 cm(-1)). The anthracenyl and pyrenyl complexes displayed bands near 390 nm (epsilon = 3.7 x 10(4) for 3 and 4.4 x 10(4) M-1 cm(-1) for 2). Complex 1 showed an emission band at 525 nm (Phi = 0.017) in 10% DMSO-DPBS (pH, 7.2), while 2 and 3 were blue emissive (lambda(em) = 440 and 435, Phi = 0.058 and 0.045). There was an enhancement in emission intensity on glutathione (GSH) addition indicating diketonate release. The platinum(II) species thus formed acted as a transcription inhibitor. The released beta-diketonate base showed photo-chemotherapeutic activity. The complexes photocleaved plasmid DNA under blue light of 457 nm forming similar to 75% nicked circular (NC) DNA with hydroxyl radicals and singlet oxygen as the ROS. Complexes 1-3 were photocytotoxic in skin keratinocyte HaCaT cells giving IC50 of 8-14 mu M under visible light (400-700 nm, 10 J cm(-2)), while being non-toxic in the dark (IC50: similar to 60 mu M). Complex 4 was inactive. Complexes 1-3 generating cellular ROS caused apoptotic cell death under visible light as evidenced from DCFDA and annexin-V/FITC-PI assays. This work presents a novel way to deliver an active platinum(II) species and a phototoxic beta-diketone species to the cancer cells

An ultra-stable redox-controlled self-assembling polypeptide nanotube for targeted imaging and therapy in cancer

We introduce a self-assembling polypeptide-based nanotube system having the ability to specifically target cancer cells. The nanotubes target the cancer cell surface through integrin engagement with the help of multiple RGD units present along their surface. While the nanotubes are non-toxic towards cells in general, they can be loaded with suitable drugs to be released in a sustained manner in cancer cells. In addition, the nanotubes can be utilized for cellular imaging using any covalently tagged fluorescent dye. They are stable over a wide range of temperature due to intermolecular disulphide bonds formed during the self-assembly process. At the same time, presence of disulphide bonds provides a redox molecular switch for their degradation. Taken together this system provides a unique avenue for multimodal formulation in cancer therapy

DDX5/p68 associated lncRNA LOC284454 is differentially expressed in human cancers and modulates gene expression

Long non-coding RNAs (lncRNAs) are emerging as important players in regulation of gene expression in higher eukaryotes. DDX5/p68 RNA helicase protein which is involved in splicing of precursor mRNAs also interacts with lncRNAs like, SRA and mrhl, to modulate gene expression. We performed RIP-seq analysis in HEK293T cells to identify the complete repertoire of DDX5/p68 interacting transcripts including 73 single exonic (SE) lncRNAs. The LOC284454 lncRNA is the second top hit of the list of SE lncRNAs which we have characterized in detail for its molecular features and cellular functions. The RNA is located in the same primary transcript harboring miR-23a approximate to 27a approximate to 24-2 cluster. LOC284454 is a stable, nuclear restricted and chromatin associated lncRNA. The sequence is conserved only in primates among 26 different species and is expressed in multiple human tissues. Expression of LOC284454 is significantly reduced in breast, prostate, uterus and kidney cancer and also in breast cancer cell lines (MCF7 and T47D). Global gene expression studies upon loss and gain of function of LOC284454 revealed perturbation of genes related to cancer-related pathways. Focal adhesion and cell migration pathway genes are downregulated under overexpression condition, and these genes are significantly upregulated in breast cancer cell lines as well as breast cancer tissue samples suggesting a functional role of LOC284454 lncRNA in breast cancer pathobiology

MOESM1 of An ultra-stable redox-controlled self-assembling polypeptide nanotube for targeted imaging and therapy in cancer

Additional file 1. Supporting Information