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Glycolytic Inhibitors Potentiated the Activity of Paclitaxel and Their Nanoencapsulation Increased Their Delivery in a Lung Cancer Model - PubMed

  • ️Sat Jan 01 2022

Glycolytic Inhibitors Potentiated the Activity of Paclitaxel and Their Nanoencapsulation Increased Their Delivery in a Lung Cancer Model

Andrea Cunha et al. Pharmaceutics. 2022.

Abstract

Antiglycolytic agents inhibit cell metabolism and modify the tumor's microenvironment, affecting chemotherapy resistance mechanisms. In this work, we studied the effect of the glycolytic inhibitors 3-bromopyruvate (3BP), dichloroacetate (DCA) and 2-deoxyglucose (2DG) on cancer cell properties and on the multidrug resistance phenotype, using lung cancer cells as a model. All compounds led to the loss of cell viability, with different effects on the cell metabolism, migration and proliferation, depending on the drug and cell line assayed. DCA was the most promising compound, presenting the highest inhibitory effect on cell metabolism and proliferation. DCA treatment led to decreased glucose consumption and ATP and lactate production in both A549 and NCI-H460 cell lines. Furthermore, the DCA pretreatment sensitized the cancer cells to Paclitaxel (PTX), a conventional chemotherapeutic drug, with a 2.7-fold and a 10-fold decrease in PTX IC50 values in A549 and NCI-H460 cell lines, respectively. To increase the intracellular concentration of DCA, thereby potentiating its effect, DCA-loaded poly(lactic-co-glycolic acid) nanoparticles were produced. At higher DCA concentrations, encapsulation was found to increase its toxicity. These results may help find a new treatment strategy through combined therapy, which could open doors to new treatment approaches.

Keywords: 2-deoxyglucose; 3-bromopyruvate; Warburg effect; dichloroacetate; nanoparticles; tumor metabolism.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1

MCT1, MCT4 and CD147 expression analysis in HPAEpic, A549 and NCI-H460 cell lines, assessed by Western blot. The noncancerous cell line HPAEpic presenting a normal phenotype was used as a reference. Levels of protein expression are relative to the control cells and were normalized against tubulin. The results are presented as means ± SD of two independent experiments. ** p < 0.01 compared to HPAEpic cells (control). &&& p < 0.001 compared to A549 cells.

Figure 2
Figure 2

Effect of GIs on cell death after 24 h of treatment with 3BP and DCA or after 48 h with 2DG. Representative cytograms (A) and quantification of Annexin V- and PI-positive cells (B) are shown for A549 (top) and NCI-H460 (bottom) cell lines. The quadrants (Q) were defined as Q1 = live (Annexin V- and PI-negative), Q2 = early stage of apoptosis (Annexin V-positive/PI-negative), Q3 = late stage of apoptosis (Annexin V- and PI-positive) and Q4 = necrosis (Annexin V-negative/PI-positive). *** p < 0.001; **** p < 0.0001 compared to untreated cells (control).

Figure 3
Figure 3

Effect of GIs on the caspase-3 activity of cells after 24 h of treatment with 3BP and DCA or after 48 h with 2DG. Quantifications were performed, normalizing the enzyme activity against the protein content of the extract and also against the value obtained in the absence of GIs. The results represent the mean ± SEM of at least three independent experiments. * p < 0.05 compared to untreated cells (control).

Figure 4
Figure 4

Metabolic profile of the lung cancer cell lines A549 and NCI-H460, estimated by (A) glucose consumption and (B) lactate and (C) ATP production, after treatment with GIs. Results are presented as means ± SEM, in triplicate, of at least three independent experiments. Significantly different between groups: * p < 0.05; ** p < 0.01; *** p < 0.001; **** p < 0.0001 compared to untreated cells (control).

Figure 5
Figure 5

Effect of GIs on cell proliferation of lung cancer cells. The cell lines were treated with the respective IC50 of 3BP and DCA for 24 h and with 2DG for 48 h. Cell proliferation was assessed through the percentage of BrdU incorporated into the DNA of the treated cells. Results represent the mean ± SEM of a least three independent experiments, each one in triplicate. ** p < 0.01; **** p < 0.0001 compared to untreated cells (control).

Figure 6
Figure 6

Effect of 3BP, DCA and 2DG at concentrations of 0 (control) and ½ IC50 on A549 and NCI-H460 cell migration (0 and 24 h of treatment) estimated by the wound-healing assay. (A,B) Photographic records of A549 and NCI-H460, respectively. (C) Quantitative results. Results represent the mean ± SEM of at least three independent experiments. Significantly different between groups: ** p < 0.01 compared to untreated cells (control).

Figure 7
Figure 7

Effect of DCA, DCA-loaded PLGA NPs and empty NPs on cell viability of A549, NCI-H460 and HPAEpic cells. SRB assay of A549, NCI-H460 and HPAEpic cells treated with 125 μg/mL of DCA, DCA-loaded PLGA NPs, or empty NPs at 24 h. Results are expressed as means ± SD of triplicates from at least three independent experiments. ** p < 0.01; *** p < 0.001 compared to DCA (control).

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