Abstract
The overexpression of ATP binding cassette (ABC) transporters makes tumor cells simultaneously resistant to several cytotoxic drugs. Impairing the energy metabolism of multidrug resistant (MDR) cells is a promising chemosensitizing strategy, but many metabolic modifiers are too toxic in vivo. We previously observed that the aminobisphosphonate zoledronic acid inhibits the activity of hypoxia inducible factor-1a (HIF-1a), a master regulator of cancer cell metabolism. Free zoledronic acid, however, reaches low intratumor concentration. We synthesized nanoparticle formulations of the aminobisphosphonate that allow a higher intratumor delivery of the drug. We investigated whether they are effective metabolic modifiers and chemosensitizing agents against human MDR cancer cells in vitro and in vivo. At not toxic dosage, nanoparticles carrying zoledronic acid chemosensitized MDR cells to a broad spectrum of cytotoxic drugs, independently of the type of ABC transporters expressed. The nanoparticles inhibited the isoprenoid synthesis and the Ras/ERK1/2-driven activation of HIF-1α, decreased the transcription and activity of glycolytic enzymes, the glucose flux through the glycolysis and tricarboxylic acid cycle, the electron flux through the mitochondrial respiratory chain, the synthesis of ATP. So doing, they lowered the ATP-dependent activity of ABC transporters, increasing the chemotherapy efficacy in vitro and in vivo. These effects were more pronounced in MDR cells than in chemosensitive ones and were due to the inhibition of farnesyl pyrophosphate synthase (FPPS), as demonstrated in FPPS-silenced tumors. Our work proposes nanoparticle formulations of zoledronic acid as the first not toxic metabolic modifiers, effective against MDR tumors.
Highlights
The mevalonate pathway produces cholesterol and isoprenoids - such as farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate - which activate small G-proteins like Ras and Rho
We investigated the effects of Zoledronic acid (ZA) and NZ in non-small cell lung cancer A549 cells and in the chemoresistant counterpart A549/multidrug resistant (MDR) cells, which had higher IC50 values towards different cytotoxic drugs (Table 1) and higher expression of different ATP binding cassette (ABC) transporters (Supplementary Figure 1)
The IC50 of ZA, NZ and self-assembling nanoparticles without ZA in A549 and A549/ MDR cells are provided in the Table 2: on the basis of these values, in all the experiments we used ZA, NZ and blank NPs at the not toxic concentration of 1 μM
Summary
The mevalonate pathway produces cholesterol and isoprenoids - such as farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate - which activate small G-proteins like Ras and Rho. The overexpression of ATP binding cassette (ABC) transporters - such as P-glycoprotein (Pgp/ABCB1), multidrug resistance related proteins (MRPs/ABCCs) and breast cancer resistance protein (BCRP/ABCG2) - limits the intracellular retention and activity of several cytotoxic drugs, producing a multidrug resistant (MDR) phenotype in tumor cells [6]. MDR cells have a higher mevalonate pathway than chemosensitive ones [7, 8]. Since the activity of ABC transporters is increased by the high content of cholesterol in the plasma membrane [7,8,9], the inhibition of mevalonate pathway has efficiently overcome the MDR phenotype in vitro [7,8,9,10,11,12,13]
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