Identification of OAT1/OAT3 as Contributors to Cisplatin Toxicity.

Cisplatin is among the most widely used anticancer drugs and known to cause a dose-limiting nephrotoxicity, which is partially dependent on the renal uptake carrier OCT2. We here report a previously unrecognized, OCT2-independent pathway of cisplatin-induced renal injury that is mediated by the organic anion transporters OAT1 and OAT3. Using transporter-deficient mouse models, we found that this mechanism regulates renal uptake of a mercapturic acid metabolite of cisplatin that acts as a precursor of a potent nephrotoxin. The function of these two transport systems can be simultaneously inhibited by the tyrosine kinase inhibitor nilotinib through noncompetitive mechanisms, without compromising the anticancer properties of cisplatin. Collectively, our findings reveal a novel pathway that explains the fundamental basis of cisplatin-induced nephrotoxicity, with potential implications for its therapeutic management.

Role of Passive Diffusion, Transporters, and Membrane Trafficking-Mediated Processes in Cellular Drug Transport.

Intracellular drug accumulation is thought to be dictated by two major processes, passive diffusion through the lipid membrane or membrane transporters. The relative role played by these distinct processes remains actively debated. Moreover, the role of membrane-trafficking in drug transport remains underappreciated and unexplored. Here we discuss the distinct processes involved in cellular drug distribution and propose that better experimental models are required to elucidate the differential contributions of various processes in intracellular drug accumulation.

Cisplatin nephrotoxicity: mechanisms and renoprotective strategies.

Cisplatin is one of the most widely used and most potent chemotherapy drugs. However, side effects in normal tissues and organs, notably nephrotoxicity in the kidneys, limit the use of cisplatin and related platinum-based therapeutics. Recent research has shed significant new lights on the mechanism of cisplatin nephrotoxicity, especially on the signaling pathways leading to tubular cell death and inflammation. Renoprotective approaches are being discovered, but the protective effects are mostly partial, suggesting the need for combinatorial strategies. Importantly, it is unclear whether these approaches would limit the anticancer effects of cisplatin in tumors. Examination of tumor-bearing animals and identification of novel renoprotective strategies that do not diminish the anticancer efficacy of cisplatin are essential to the development of clinically applicable interventions.

The distribution and myotropic activity of locustatachykinin-like peptides in locust midgut.

The midgut of the African migratory locust, Locusta migratoria, was found to contain endocrine-like cells that stained positively for locustatachykinin I (Lom TK I)-like immunoreactivity. These cells were distributed in an unequal manner throughout the midgut of the locust, with a greater density of Lom TK I-like immunoreactive endocrine-like cells occurring in the posterior region of the midgut. These singly occurring cells appear elongate with an apical extension projecting toward the midgut lumen and a smaller projection extending towards the midgut basal lamina. No immunoreactive neuronal processes were detected along the midgut wall. Radioimmunoassays revealed that the female midgut contained two to three times more Lom TK I-like material than the male midgut, and radioimmunoassay coupled to high-performance liquid chromatography analysis revealed that at least five locustatachykinin isoforms appear to be present in the midgut. This distribution of Lom TK I-like material suggests possible functional differences in the various regions of the midgut. The role that these cells may play in locust midgut secretory activity and motility remains unknown. However, the addition of synthetic Lom TK I through IV to a ring type midgut muscle preparation stimulated contraction of midgut circular muscles, suggesting a possible physiological role for these peptides. Dose-response curves constructed for Lom TK I-IV revealed that the peptide-induced contractions increased in a dose-dependent manner.