Nongenomic Effects of Cisplatin: Acute Inhibition of Mechanosensitive Transporters and Channels without Actin Remodeling

Abstract

Cisplatin is an antineoplastic drug, mostly documented to cause cell death through the formation of DNA adducts. In patients, it exhibits a range of short-term side effects that are unlikely to be related to its genomic action. As cisplatin has been shown to modify membrane properties in different cell systems, we investigated its effects on mechanosensitive ion transporters and channels. We show here that cisplatin is a noncompetitive inhibitor of the mechanosensitive Na + /H + exchanger NHE-1, with a half-inhibition concentration of 30 μg/mL associated with a decrease in V max and Hill coefficient. We also showed that it blocks the Cl − and K + mechanosensitive channels VSORC and TREK-1 at similar concentrations. In contrast, the nonmechanosensitive Cl − and K + channels CFTR and TASK-1 and the Na + -coupled glucose transport, which share functional features with VSORC, TREK-1, and NHE-1, respectively, were insensitive to cisplatin. We next investigated whether cisplatin action was due to a direct effect on membrane or to cortical actin remodeling that would affect mechanosensors. Using scanning electron microscopy, in vivo actin labeling, and atomic force microscopy, we did not observe any modification of the Young's modulus and actin cytoskeleton for up to 60 and 120 μg/mL cisplatin, whereas these concentrations modified membrane morphology. Our results reveal a novel mechanism for cisplatin, which affects mechanosensitive channels and transporters involved in cell fate programs and/or expressed in mechanosensitive organs in which cisplatin elicits strong secondary effects, such as the inner ear or the peripheral nervous system. These results might constitute a common denominator to previously unrelated effects of this drug.

Mechanics of the Toxoplasma gondii oocyst wall

“…This tip can be used to: (i) delineate the surface (imaging mode; refs. [34][35][36], (ii) indent objects' surface by pressing on them and allowing measurement of their mechanical properties (force mode, mechanics) (37)(38)(39)(40), or (iii) probe the adhesion of surface molecules when decorated with suitable haptens and pulling the lever off the surface until all built bridges are broken. This allows direct quantifying of the force that these bridges can sustain (force mode, adhesion).…”

FRAKSI ETIL ASETAT KULIT BATANG FALOAK (Sterculia quadrifida R.Br ) MENGINDUKSI APOPTOSIS DAN SIKLUS SEL PADA SEL KANKER PAYUDARA T47D

“…Agen kemoterapi yang sering digunakan dalam terapi kanker payudara adalah cisplatin (Dhar et al, 2011). Cisplatin menimbulkan efek samping antara lain: neurotoksisitas, nefrotoksisitas (Milosavlievic et al, 2010), dan bone marrow suppression. Selain itu dilaporkan juga bahwa penggunaan cisplatin menyebabkan terjadinya resistensi.…”

Functional Characterization of Na⁺/H⁺ Exchangers of Intracellular Compartments Using Proton-killing Selection to Express Them at the Plasma Membrane

“…7. Measure the lithium content of the supernatants by atomic absorption spectroscopy 21 . NOTE: Different companies provide atomic absorption spectrometers, which have to be equipped with a Lithium hollow cathode lamp.…”

“…be measured with great accuracy using atomic absorption spectrometry 21 . Once the appropriate conditions (time and lithium concentration) to measure linear uptakes (i.e., being in initial rates conditions) are determined, affinities for the other potential coupling cations and/or inhibitors can be accurately measured as shown in Figures 3 and 4. A last potential limitation is that the lithium uptake method can of course only function if the exchanger of interest significantly transports this cation.…”