Low Intensity Ultrasound Promotes the Sensitivity of Rat Brain Glioma to Doxorubicin by Down-Regulating the Expressions of P-Glucoprotein and Multidrug Resistance Protein 1 In Vitro and In Vivo

Abstract

The overall prognosis for malignant glioma is extremely poor, and treatment options are limited in part because of multidrug resistant proteins. Our previous findings suggest low intensity ultrasound (LIUS) can induce apoptosis of glioma cells. Given this finding, we were interested in determining if LIUS could help treat glioma by inhibiting multidrug resistant proteins, and if so, which pathways are involved. In this study, the toxicity sensitivity and multidrug resistance proteins of glioma induced by LIUS were investigated using CCK-8, immunohistochemistry, immunofluorency, and RT-PCR in tissue samples and cultured cells. LIUS inhibited increase of C6 cells in an intensity- and time-dependent manner. The toxicity sensitivity of C6 cells increased significantly after LIUS sonication (intensity of 142.0 mW/cm2) or Doxorubicin (DOX) at different concentration, particularly by the combination of LIUS sonication and DOX. The expressions of P-gp and MRP1 decreased significantly post-sonication at intensity of 142.0 mW/cm2 both in vitro and in vivo. The expressions of p110 delta (PI3K), NF-κB-p65, Akt/PKB, and p-Akt/PKB were downregulated by LIUS sonication and DOX treatment separately or in combination at the same parameters in rat glioma. These results indicate that LIUS could increase the toxicity sensitivity of glioma by down-regulating the expressions of P-gp and MRP1, which might be mediated by the PI3K/Akt/NF-κB pathway.

Timosaponin A-III reverses multi-drug resistance in human chronic myelogenous leukemia K562/ADM cells via downregulation of MDR1 and MRP1 expression by inhibiting PI3K/Akt signaling pathway

“…are ABC transporters, which are overexpressed in many drug-resistant cells (8,12,13). K562/ADM cells express higher levels of P-gp and MRP1 than K562 cells (26,28).…”

“…The phosphoinositide 3-kinase/serine-threonine kinase (PI3K/Akt) signaling pathway is a well-known fundamental intracellular signaling transduction pathway involved in multiple biological processes both in normal and cancer cells, including gene transcription and translation, cell growth, proliferation and survival, cell metabolism, cell cycle progression, apoptosis and autophagy (8)(9)(10). Besides, there is an increasing amount of preclinical data supporting that the PI3K/Akt signaling pathway is also involved in the drug resistance of different types of human malignant cells, including CML (2,4,5,(12)(13)(14)(15).…”

Effects on P-Glycoprotein Expression after Blood-Brain Barrier Disruption Using Focused Ultrasound and Microbubbles

“…It is possible that it also could suppress drug efflux pumps such as Pgp. Indeed, others have shown in other contexts that ultrasound effects can suppress Pgp [29–33] but only limited studies have investigated this effect in CNS capillaries [34,35]. Here, we set out to characterize the possible interaction between the FUS exposures and Pgp expression in the BBB at different time points after sonication.…”

Evaluation of permeability, doxorubicin delivery, and drug retention in a rat brain tumor model after ultrasound-induced blood-tumor barrier disruption

“…It is possible that the sonications resulted in suppression of one or more drug efflux pumps. Indeed, others have shown that the efflux pump P-glycoprotein can be suppressed by ultrasound [42,43], and our laboratory has reported that such suppression may occur in blood vessels in the brain after BBB disruption [44]. DOX is known to be a substrate for P-glycoprotein.…”