Also published as: Cecília M. P. Rodrigues, Daniel A Rodrigues, Daniel A. Rodrigues, Daniel Alencar Rodrigues, M. I. Rodrigues, M. Rodrigues, N.R. Rodrigues
It is well established that oxaliplatin, one of the three Pt(II) anticancer drugs approved worldwide, and phenanthriplatin, an important preclinical monofunctional Pt(II) anticancer drug, possess a di Show more
It is well established that oxaliplatin, one of the three Pt(II) anticancer drugs approved worldwide, and phenanthriplatin, an important preclinical monofunctional Pt(II) anticancer drug, possess a different mode of action from that of cisplatin and carboplatin, namely, the induction of nucleolar stress. The exact mechanisms that lead to Pt-induced nucleolar stress are, however, still poorly understood. As such, studies aimed at better understanding the biological targets of both oxaliplatin and phenanthriplatin are urgently needed to expand our understanding of Pt-induced nucleolar stress and guide the future design of Pt chemotherapeutics. One approach that has seen great success in the past is the use of Pt-click complexes to study the biological targets of Pt drugs. Herein, we report the synthesis and characterization of the first examples of click-capable phenanthriplatin complexes. Furthermore, through monitoring the relocalization of nucleolar proteins, RNA transcription levels, and DNA damage repair biomarker γH2AX, and by investigating their in vitro cytotoxicity, we show that these complexes successfully mimic the cellular responses observed for phenanthriplatin treatment in the same experiments. The click-capable phenanthriplatin derivatives described here expand the existing library of Pt-click complexes. Significantly they are suitable for studying nucleolar stress mechanisms and further elucidating the biological targets of Pt complexes. Show less
Abstract Imaging contrast agents are widely investigated in preclinical and clinical studies, among which biogenic imaging contrast agents (BICAs) are developing rapidly and playing an increasingly i Show more
Abstract Imaging contrast agents are widely investigated in preclinical and clinical studies, among which biogenic imaging contrast agents (BICAs) are developing rapidly and playing an increasingly important role in biomedical research ranging from subcellular level to individual level. The unique properties of BICAs, including expression by cells as reporters and specific genetic modification, facilitate various in vitro and in vivo studies, such as quantification of gene expression, observation of protein interactions, visualization of cellular proliferation, monitoring of metabolism, and detection of dysfunctions. Furthermore, in human body, BICAs are remarkably helpful for disease diagnosis when the dysregulation of these agents occurs and can be detected through imaging techniques. There are various BICAs matched with a set of imaging techniques, including fluorescent proteins for fluorescence imaging, gas vesicles for ultrasound imaging, and ferritin for magnetic resonance imaging. In addition, bimodal and multimodal imaging can be realized through combining the functions of different BICAs, which helps overcome the limitations of monomodal imaging. In this review, the focus is on the properties, mechanisms, applications, and future directions of BICAs. Show less
Summary The treatment of colorectal cancer (CRC) with FOLFOX shows some efficacy, but these tumors quickly develop resistance to this treatment. We have observed increased phosphorylation of AKT1/mTO Show more
Summary The treatment of colorectal cancer (CRC) with FOLFOX shows some efficacy, but these tumors quickly develop resistance to this treatment. We have observed increased phosphorylation of AKT1/mTOR/4EBP1 and levels of p21 in FOLFOX-resistant CRC cells. We have identified a small molecule, NSC49L, that stimulates protein phosphatase 2A (PP2A) activity, downregulates the AKT1/mTOR/4EBP1-axis, and inhibits p21 translation. We have provided evidence that NSC49L- and TRAIL-mediated sensitization is synergistically induced in p21-knockdown CRC cells, which is reversed in p21-overexpressing cells. p21 binds with procaspase 3 and prevents the activation of caspase 3. We have shown that TRAIL induces apoptosis through the activation of caspase 3 by NSC49L-mediated downregulation of p21 translation, and thereby cleavage of procaspase 3 into caspase 3. NSC49L does not affect global protein synthesis. These studies provide a mechanistic understanding of NSC49L as a PP2A agonist, and how its combination with TRAIL sensitizes FOLFOX-resistant CRC cells. Show less
The role of copper in the proliferation of cancer cells is under investigation and has been explored in the context of cancer chemotherapy. The evidence that proliferation of cancer cells requires a h Show more
The role of copper in the proliferation of cancer cells is under investigation and has been explored in the context of cancer chemotherapy. The evidence that proliferation of cancer cells requires a higher abundance of Cu(II) than their normal counterparts has prompted the development of new copper chelators that can avidly bind copper ions, forming redox active metal complexes that ultimately lead to harmful reactive oxygen species (ROS) in neoplasms. In this context, the mandatory properties of the chelators for medical applications are safety (neglectable cytotoxicity), high binding affinity and selectivity towards Cu(II). We report the synthesis, structure (calculations and single crystal X-ray diffraction), spectroscopic (IR; UV-Vis) and magnetic properties of two novel copper(II) complexes based on 5-(3-aminosaccharyl)-tetrazoles (TS and 2MTS), as well as their in vitro cytotoxicity against the human hepatic carcinoma cell line HepG2. Quite interestingly, we found that the saccharinate-tetrazoles tested exhibit strong binding selectivity to Cu(II), over Fe(II) and Ca(II). Additionally, the corresponding copper complexes have shown a huge increase in the in vitro cytotoxicity against tumoral cells, compared to the corresponding nontoxic ligands. Thus, the new ligands may be viewed as potential precursors of selective cytotoxic agents, acting as non-cytotoxic pro-drugs that can be activated inside neoplastic cells, known to be richer in Cu(II) than the corresponding normal cells. Show less