Bidentate Ligands on Osmium(VI) Nitrido Complexes Control Intracellular Targeting and Cell Death Pathways

The cellular response evoked by antiproliferating osmium­(VI) nitrido compounds of general formula OsN­(N^N)­Cl₃ (N^N = 2,2′-bipyridine <b>1</b>, 1,10-phenanthroline <b>2</b>, 3,4,7,8-tetramethyl-1,10-phenanthroline <b>3</b>, or 4,7-diphenyl-1,10-phenanthroline <b>4</b>) can be tuned by subtle ligand modifications. Complex <b>2</b> induces DNA damage, resulting in activation of the p53 pathway, cell cycle arrest at the G2/M phase, and caspase-dependent apoptotic cell death. In contrast, <b>4</b> evokes endoplasmic reticulum (ER) stress leading to the upregulation of proteins of the unfolded protein response pathway, increase in ER size, and p53-independent apoptotic cell death. To the best of our knowledge, <b>4</b> is the first osmium compound to induce ER stress in cancer cells

Bidentate Ligands on Osmium(VI) Nitrido Complexes Control Intracellular Targeting and Cell Death Pathways

The cellular response evoked by antiproliferating osmium­(VI) nitrido compounds of general formula OsN­(N^N)­Cl₃ (N^N = 2,2′-bipyridine <b>1</b>, 1,10-phenanthroline <b>2</b>, 3,4,7,8-tetramethyl-1,10-phenanthroline <b>3</b>, or 4,7-diphenyl-1,10-phenanthroline <b>4</b>) can be tuned by subtle ligand modifications. Complex <b>2</b> induces DNA damage, resulting in activation of the p53 pathway, cell cycle arrest at the G2/M phase, and caspase-dependent apoptotic cell death. In contrast, <b>4</b> evokes endoplasmic reticulum (ER) stress leading to the upregulation of proteins of the unfolded protein response pathway, increase in ER size, and p53-independent apoptotic cell death. To the best of our knowledge, <b>4</b> is the first osmium compound to induce ER stress in cancer cells

Correction to “A Pt(IV) Pro-drug Preferentially Targets Indoleamine-2,3-dioxygenase, Providing Enhanced Ovarian Cancer Immuno-Chemotherapy”

Correction to “A Pt(IV) Pro-drug Preferentially Targets Indoleamine-2,3-dioxygenase, Providing Enhanced Ovarian Cancer Immuno-Chemotherapy

A Breast Cancer Stem Cell-Selective, Mammospheres-Potent Osmium(VI) Nitrido Complex

The effect of a newly developed osmium(VI) nitrido complex, <b>1</b>, on breast cancer stem cells (CSCs) is reported. The complex displays selective toxicity for HMLER breast cancer cells enriched with CD44-positive, CSC-like cells over the same cells having reduced CSC character. Remarkably, <b>1</b> also reduces the proportion of CSCs within a heterogeneous breast cancer cell population and irreversibly inhibits the formation of free-floating mammo­spheres to an extent similar to that of salino­mycin, a natural product that targets CSCs. Detailed mechanistic studies reveal that in breast cancer cells <b>1</b> induces DNA damage and endoplasmic reticulum stress, the latter being responsible for the CSC selectivity. The anti-CSC properties of <b>1</b> provide a strong impetus for the development of new metal-based compounds to target CSCs and to treat chemotherapy-resistant and relapsed tumors

Using an RNAi Signature Assay To Guide the Design of Three-Drug-Conjugated Nanoparticles with Validated Mechanisms, In Vivo Efficacy, and Low Toxicity

Single-nanoparticle (NP) combination chemotherapeutics are quickly emerging as attractive alternatives to traditional chemotherapy due to their ability to increase drug solubility, reduce off-target toxicity, enhance blood circulation lifetime, and increase the amount of drug delivered to tumors. In the case of NP-bound drugs, that is, NP-prodrugs, the current standard of practice is to assume that the subcellular mechanism of action for each drug released from the NP mirrors that of the unbound, free-drug. Here, we use an RNAi signature assay for the first time to examine the mechanism of action of multidrug-conjugated NP prodrugs relative to their small molecule prodrugs and native drug mechanisms of action. Additionally, the effective additive contribution of three different drugs in a single-NP platform is characterized. The results indicate that some platinum­(IV) cisplatin prodrugs, although cytotoxic, may not have the expected mechanism of action for cisplatin. This insight was utilized to develop a novel platinum­(IV) oxaliplatin prodrug and incorporate it into a three-drug-conjugated NP, where each drug’s mechanism of action is preserved, to treat tumor-bearing mice with otherwise lethal levels of chemotherapy