ABTL0812 enhances antitumor effect of paclitaxel and reverts chemoresistance in triple-negative breast cancer models

Emma Polonio-Alcalá, Sònia Solé-Sánchez, Pau Muñoz-Guardiola, Elisabet Megías-Roda, Héctor Perez-Montoyo, Marc Yeste-Velasco, Jose Alfón, Jose Miguel Lizcano, Carles Domènech, Santiago Ruiz-Martínez, Teresa Puig, Emma Polonio-Alcalá, Sònia Solé-Sánchez, Pau Muñoz-Guardiola, Elisabet Megías-Roda, Héctor Perez-Montoyo, Marc Yeste-Velasco, Jose Alfón, Jose Miguel Lizcano, Carles Domènech, Santiago Ruiz-Martínez, Teresa Puig

No abstract available

Keywords: ABTL0812; Autophagy; Breast Cancer; Chemoresistance; TRIB3; Targeted Therapy.

Conflict of interest statement

Sònia Solé‐Sánchez, Pau Muñoz‐Guardiola, Elisabet Megías‐Roda, Héctor Perez‐Montoyo, Marc Yeste‐Velasco, Jose Alfón, and Carles Domènech are Ability Pharmaceuticals employees; Jose Miguel Lizcano is an advisory board member and Carles Domènech holds shares of the company.

Figures

FIGURE 1

ABTL0812 has anticancer activity in sensitive and paclitaxel‐resistant TNBC cell models, enhances paclitaxel activity and reverts resistance to paclitaxel. (A) Representative images of protein levels of TRIB3 and LC3‐I/II were obtained by western blotting analysis of ABTL0812 treatment for 24 hours in MDA‐MB‐231 and 231PTR cells. (B) Cell proliferation effect of paclitaxel alone and in combination with different concentrations of ABTL0812 (5, 10, and 20 μmol/L) for 48 hours in MDA‐MB‐231 and 231PTR cells. The dotted line indicates 50% of cell proliferation. Levels of statistical significance are indicated as *P < 0.05 and **P < 0.010 compared to the anti‐cell proliferation effect of paclitaxel alone. (C) Representation of the CI of all ABTL0812 and paclitaxel combinations at different concentrations. The dotted line indicates when CI is 1 (additive effect). CI > 1 is considered antagonistic and <1, synergistic. The data are represented as the CI versus different paclitaxel doses for each concentration of ABTL0812 (5, 10 and 20 μmol/L). Levels of statistical significance are indicated as *P < 0.05 and **P < 0.010 compared to the value 1. (D) Protein levels of TRIB3 and LC3 determined by western blotting analyses of paclitaxel alone and in combination with ABTL0812 for 48 hours in MDA‐MB‐231 and 231PTR cells. Representative graphs and images are shown. Equivalent results were found in at least three independent experiments. (E) Study of the tumor growth of a subcutaneous murine xenograft model generated by inoculation of 231PTR cells. ABTL0812 was administered orally every day at a dose of 120 mg/kg; paclitaxel was intraperitoneally administered at 10 mg/kg once a week. Each data point represents tumor volume average and SEM from each group of animals. * indicates the statistical significance level of the comparison between ABTL0812 + paclitaxel and vehicle, and # between paclitaxel and vehicle (*P < 0.05; ** P <0.01; ***P < 0.001). (F) TRIB3 and LC3 I/II protein levels were determined in three to four different animals of each treatment group by western blot of xenograft tumor lysates at day 36. The image is from one representative western blot experiment. Abbreviations: TRIB3, Tribbles homolog 3; LC3, Microtubule‐associated protein 1A/1B‐light chain 3; TNBC, Triple‐negative breast cancer; 231PTR, Paclitaxel‐resistant MDA‐MB‐231 cells; CI, Combination index; SEM, Standard error of the mean.