Overexpression of P-glycoprotein (P-gp) and other ATP-binding cassette (ABC) transporters in multidrug resistant (MDR) cancer cells is responsible for the reduction of intracellular drug accumulation, thus decreasing the efficacy of chemotherapeutics. P-gp is also found at endothelial cells’ membrane of the blood-brain barrier, where it limits drug delivery to central nervous system (CNS) tumors. We have previously developed a set of pyrazolo[3,4-d]pyrimidines and their prodrugs as novel Src tyrosine kinase inhibitors (TKIs), showing a significant activity against CNS tumors in in vivo. Here we investigated the interaction of the most promising pair of drug/prodrug with P-gp at the cellular level. The tested compounds were found to increase the intracellular accumulation of Rho 123, and to enhance the efficacy of paclitaxel in P-gp overexpressing cells. Encouraging pharmacokinetics properties and tolerability in vivo were also observed. Our findings revealed a novel role of pyrazolo[3,4-d]pyrimidines which may be useful for developing a new effective therapy in MDR cancer treatment, particularly against glioblastoma.
Cytotoxicity screenings
have identified
Plectranthus
plants as potential
sources of antitumor lead compounds. In this
work, several extracts from
Plectranthus madagascariensis
were prepared using different solvents (acetone, methanol, and supercritical
CO
2
) and extraction techniques (maceration, ultrasound-assisted,
and supercritical fluid extraction), and their chemical composition
was detailed using high-performance liquid chromatography with a diode
array detector. The cytotoxic activity of the major compounds identified,
namely, rosmarinic acid (
1
) and abietane diterpenes 7α,6β-dihydroxyroyleanone
(
2
), 7α-formyloxy-6β-hydroxyroyleanone (
3
), 7α-acetoxy-6β-hydroxyroyleanone (
4
), and coleon U (
5
), was evaluated in a battery of human
cancer cell lines, including breast (MDA-MB-231, MCF-7), colon (HCT116),
and lung (NCI-H460, NCI-H460/R) cancer, and also in healthy lung (MCR-5)
cells. Royleanone (
3
) was isolated for the first time
from
P. madagascariensis
, and its full
spectroscopic characterization (proton and carbon nuclear magnetic
resonance) was accomplished. A high selectivity for lung cancer cells
was observed for royleanones (
2
,
4
) with
selectivity indexes of 4.3 and 3.2, respectively. The observed results
combined with literature data allowed the establishment of important
structure–activity relationships for substituted royleanone
abietanes, such as the requirement for an electron-donating group
at positions 6 and/or 7 in the abietane skeleton, and an improved
cytotoxic effect for substituents with log
P
values
between 2 and 5.
The main reasons for the inefficiency of standard glioblastoma (GBM) therapy are the occurrence of chemoresistance and the invasion of GBM cells into surrounding brain tissues. New therapeutic approaches obstructing these processes may provide substantial survival improvements. The purpose of this study was to assess the potential of lipophilic antioxidant coenzyme Q10 (CoQ10) as a scavenger of reactive oxygen species (ROS) to increase sensitivity to temozolomide (TMZ) and suppress glioma cell invasion. To that end, we used a previously established TMZ-resistant RC6 rat glioma cell line, characterized by increased production of ROS, altered antioxidative capacity, and high invasion potential. CoQ10 in combination with TMZ exerted a synergistic antiproliferative effect. These results were confirmed in a 3D model of microfluidic devices showing that the CoQ10 and TMZ combination is more cytotoxic to RC6 cells than TMZ monotherapy. In addition, cotreatment with TMZ increased expression of mitochondrial antioxidant enzymes in RC6 cells. The anti-invasive potential of the combined treatment was shown by gelatin degradation, Matrigel invasion, and 3D spheroid invasion assays as well as in animal models. Inhibition of MMP9 gene expression as well as decreased N-cadherin and vimentin protein expression implied that CoQ10 can suppress invasiveness and the epithelial to mesenchymal transition in RC6 cells. Therefore, our data provide evidences in favor of CoQ10 supplementation to standard GBM treatment due to its potential to inhibit GBM invasion through modulation of the antioxidant capacity.
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