The initiating mutations that contribute to cancer development are sometimes present in premalignant cells. Whether therapies targeting these mutations can eradicate premalignant cells is unclear. Acute myeloid leukemia (AML) is an attractive system for investigating the effect of preventative treatment because this disease is often preceded by a premalignant state (clonal hematopoiesis or myelodysplastic syndrome). In Npm1c/Dnmt3a mutant knock-in mice, a model of AML development, leukemia is preceded by a period of extended myeloid progenitor cell proliferation and self-renewal. We found that this self-renewal can be reversed by oral administration of a small molecule (VTP-50469) that targets the MLL1-Menin chromatin complex. These preclinical results support the hypothesis that individuals at high risk of developing AML might benefit from targeted epigenetic therapy in a preventative setting.

Oxaliplatin is an integral component of colorectal cancer therapy, but its clinical use is associated with a dose-limiting peripheral neurotoxicity. We found that the organic cation transporter 2 (OCT2) is expressed on dorsal root ganglia cells within the nervous system where oxaliplatin is known to accumulate. Cellular uptake of oxaliplatin was increased by 16-to 35-fold in cells overexpressing mouse Oct2 or human OCT2, and this process was associated with increased DNA platination and oxaliplatin-induced cytotoxicity. Furthermore, genetic or pharmacologic knockout of Oct2 protected mice from hypersensitivity to cold or mechanical-induced allodynia, which are established tests to assess acute oxaliplatin-induced neurotoxicity. These findings provide a rationale for the development of targeted approaches to mitigate this debilitating toxicity.neuropathy | chemotherapy | solute carriers

New stable cationic organogold(III) complexes containing the 'pincer' iminophosphorane ligand (2-C 6 H 4 -PPh 2 =NPh) have been prepared by reaction of the previously described [Au{κ 2 -C,N-C 6 H 4 (PPh 2 =N(C 6 H 5 )-2}Cl 2 ] 1 and a combination of sodium or silver salts and appropriate ligands. The presence of the P atom in the PR 3 fragment has been used as a "spectroscopic marker" to study the in vitro stability (and oxidation state) of the new organogold complexes in solvents like DMSO and water. Compounds with dithiocarbamato ligands and water-soluble phosphines of the general type [Au{κ 2 -C,NC 6 H 4 (PPh 2 =N(C 6 H 5 )-2}(S 2 CN-R 2 )]PF 6 (R = Me 2; Bz 3) and [Au{κ 2 -C,N-C 6 H 4 (PPh 2 =N(C 6 H 5 )-2}(PR 3 ) n Cl]PF 6 (PR 3 = P{Cp(m-C 6 H 4 -SO 3 Na) 2 } n = 1 4, n = 2 TPA {1,3,5-triaza-7-phosphaadamantane} 5) have been synthesized and characterized in solution and in the solid state (the crystal structure of 2 has been determined by X-ray diffraction studies). Complexes 1-5 have been tested as potential anticancer agents and their cytotoxicity properties were evaluated in vitro against HeLa human cervical carcinoma and Jurkat-T acute lymphoblastic leukemia cells. Compounds 2 and 3 are quite cytotoxic for these two cell lines. There is a preferential induction of apoptosis in HeLa cells after treatment with 1-5. However in the case of the more cytotoxic complex (2), cell death is activated due to both apoptosis and necrosis. The interactions of 1-5 with Calf Thymus DNA have been evaluated by Thermal Denaturation methods. All these complexes show no or little (electrostatic) interaction with DNA. The interaction of 2 with two model proteins (cytochrome c and thioredoxin reductase) has been analyzed by spectroscopic methods (vis-UV and fluorescence). Compound 2 manifests a high reactivity toward both proteins. The mechanistic implications of these results are discussed here.