👤 Park MT

The photo-induced CO-releasing properties of the dark-stable complex [RuCl₂(CO)₂L] (L = 2-(pyridin-2-yl)quinoxaline) were investigated under 468 nm light exposure in the presence and absence of biomolecules such as histidine, calf thymus DNA and hen egg white lysozyme. The CO release kinetics were consistent regardless of the presence of these biomolecules, suggesting that they did not influence the CO release mechanism. The quinoxaline ligand demonstrated exceptional cytotoxicity against human acute monocytic leukemia cells (THP-1), with evidence of potential DNA damage ascertained by comet assay, while it remained non-toxic to normal kidney epithelial cells derived from African green monkey (Vero) cell lines. In contrast, upon light activation, the Ru(II) complex showed no toxicity against THP-1 cells but was detrimental to Vero cells. In human colorectal carcinoma (HCT-116) cells, the ligand and the Ru(II) complex produced ROS under light and dark conditions. However, HCT-116 cells retained their ability to consume oxygen and produce ATP following CO treatment, suggesting that the ROS levels were insufficient to cause significant cellular damage. Morphological features of apoptosis, including apoptotic bodies, chromatin condensation, cell shrinkage, and membrane leakage, were observed in the presence of both the ligand and its complex, irrespective of light exposure. Show less

Dysregulation of Fibroblast Growth Factor Receptors (FGFRs) signaling has been associated with breast cancer, yet employing FGFR-targeted delivery systems to improve the efficacy of cytotoxic agents is still sparsely exploited. Herein, we report four new bi-functional ruthenium-peptide conjugates (RuPCs) with FGFR-targeting and pH-dependent releasing abilities, envisioning the selective delivery of cytotoxic Ru complexes to FGFR(+)-breast cancer cells, and controlled activation at the acidic tumoral microenvironment. The antiproliferative potential of the RuPCs and free Ru complexes was evaluated in four breast cancer cell lines with different FGFR expression levels (SKBR-3, MDA-MB-134-VI, MCF-7, and MDA-MB-231) and in human dermal fibroblasts (HDF), at pH 6.8 and pH 7.4 aimed at mimicking the tumor microenvironment and normal tissues/bloodstream pHs, respectively. The RuPCs showed higher cytotoxicity in cells with higher level of FGFR expression at acidic pH. Additionally, RuPCs showed up to 6-fold higher activity in the FGFR(+) breast cancer lines compared to the normal cell line. The release profile of Ru complexes from RuPCs corroborates the antiproliferative effects observed. Remarkably, the cytotoxicity and releasing ability of RuPCs were shown to be strongly dependent on the conjugation of the peptide position in the Ru complex. Complementary molecular dynamic simulations and computational calculations were performed to help interpret these findings at the molecular level. In summary, we identified a lead bi-functional RuPC that holds strong potential as a FGFR-targeted chemotherapeutic agent. Show less

Two bifunctional ruthenium(II)-p-cymene complexes with perfluorinated side chains, attached via pyridine ligands, have been evaluated in a series of in vitro and in vivo assays. Their effects on human endothelial (ECRF24 and HUVEC) cells, noncancerous human embryonic kidney (HEK-293) cells, and various human tumor cells were investigated. The complex with the shorter chain, 1, inhibits the proliferation of the tumor cell lines and ECRF24, whereas 2 selectively inhibits ECRF24 and HUVEC proliferation. Neither inhibits the migration of ECRF24 cells whereas both compounds inhibit sprout formation in HUVEC cells. Using three preclinical models, i.e., vasculature formation in the chorioallantoic membrane (CAM) of the chicken embryo, human A2780 ovarian carcinoma tumors xenografted on the CAM, and human LS174T colorectal adenocarcinoma tumors grown in athymic mice, the angiostatic and anticancer activities of these two complexes were studied. Overall, 1 inhibited tumor growth predominantly through an anticancer effect whereas 2 inhibited tumor growth predominately via an antiangiogenic mechanism. Show less

Reactive oxygen species (ROS) are well known to be involved in oncogene-mediated cellular transformation. However, the regulatory mechanisms underlying ROS generation in oncogene-transformed cells are unclear. In the present study, we found that oncogenic K-Ras induces ROS generation through activation of NADPH oxidase 1 (NOX1), which is a critical regulator for the K-Ras-induced cellular transformation. NOX1 was activated by K-Ras-dependent translocation of p47(phox), a subunit of NOX1 to plasma membrane. Of note, PKCδ, when it was activated by PDPK1, directly bound to the SH3-N domain of p47(phox) and catalyzed the phosphorylation on Ser348 and Ser473 residues of p47(phox) C-terminal in a K-Ras-dependent manner, finally leading to its membrane translocation. Notably, oncogenic K-Ras activated all MAPKs (JNK, ERK and p38); however, only p38 was involved in p47(phox)-NOX1-dependent ROS generation and consequent transformation. Importantly, K-Ras-induced activation of p38 led to an activation of PDPK1, which then signals through PKCδ, p47(phox) and NOX1. In agreement with the mechanism, inhibition of p38, PDPK1, PKCδ, p47(phox) or NOX1 effectively blocked K-Ras-induced ROS generation, anchorage-independent colony formation and tumor formation. Taken together, our findings demonstrated that oncogenic K-Ras activates the signaling cascade p38/PDPK1/PKCδ/p47(phox)/NOX1 for ROS generation and consequent malignant cellular transformation. Show less