Mimicking Retinoblastoma Treatment With Repeated Topotecan or Melphalan Develops Cross-Resistance to Classic Agents But Not to Repurposed Drugs
Por:
Cancela MB, Winter U, Zugbi S, Dinardi M, Alves da Quinta D, Aschero MR, Ganiewich D, Sampor C, Sgroi M, Lagomarsino E, Fandiño A, Llera AS, Chantada G, Carcaboso AM and Schaiquevich P
Publicada:
1 dic 2024
Resumen:
PURPOSE. Refractory or recurrent retinoblastoma results from acquired chemoresistance and the management of these eyes often requires surgical removal. Our objective was to develop retinoblastoma models resistant to chemotherapy by exposing cancer cells to repeated chemotherapy mimicking the clinical scenario. These newly resistant cells were used to evaluate potential novel therapies. METHODS. Chemoresistant cells were obtained by exposing two primary retinoblastoma cell cultures to three weekly doses of melphalan or topotecan. The sensitivity of these resistant cells to each chemotherapy was evaluated, and cross-resistance to topotecan, melphalan, and carboplatin was assessed. Genomic alterations and differential expression of efflux/influx transporters between chemoresistant and parental cells were analyzed. Subsequently, sensitivity of both resistant and parental cells to the repurposed agents digoxin, methylene blue, and gemcitabine was assessed. RESULTS. Four chemoresistant models were successfully established, showing significantly higher half-maximal inhibitory concentration (IC50) values for melphalan and topotecan compared to their corresponding parental cells (P < 0.05). Cross-resistance between melphalan and topotecan was demonstrated, with a 3-fold increase in the IC50. Chemoresistant cells also showed reduced sensitivity to carboplatin (P < 0.05) compared to parental cells, whereas sensitivity to the evaluated repurposed agents remained unchanged. Genomic analysis revealed no selective alterations in the resistant cells, although differential expression of influx/efflux transporters was observed across all chemoresistant models. CONCLUSIONS. In vitro simulation of patient treatment was useful to establish chemoresistant retinoblastomas and to identify strategies to overcome resistance to topotecan or melphalan through drug repurposed. Our results warrant further investigation to support the clinical translation.
Filiaciones:
Cancela MB:
Unit of Innovative Treatments, Hospital de Pediatría JP Garrahan, Buenos Aires, Argentina
National Scientific and Technical Research Council, CONICET, Buenos Aires, Argentina
Winter U:
National Scientific and Technical Research Council, CONICET, Buenos Aires, Argentina
Zugbi S:
Unit of Innovative Treatments, Hospital de Pediatría JP Garrahan, Buenos Aires, Argentina
National Scientific and Technical Research Council, CONICET, Buenos Aires, Argentina
Dinardi M:
Unit of Innovative Treatments, Hospital de Pediatría JP Garrahan, Buenos Aires, Argentina
Alves da Quinta D:
National Scientific and Technical Research Council, CONICET, Buenos Aires, Argentina
Laboratory of Molecular and Cellular Therapy, Instituto Leloir - Instituto de Investigaciones Bioquímicas de Buenos Aires (IIBBA), Buenos Aires, Argentina
Aschero MR:
SJD Pediatric Cancer Center Barcelona, Hospital Sant Joan de Deu, Barcelona, Spain
Institut de Recerca Sant Joan de Déu, Barcelona, Spain
Ganiewich D:
Laboratory of Molecular and Cellular Therapy, Instituto Leloir - Instituto de Investigaciones Bioquímicas de Buenos Aires (IIBBA), Buenos Aires, Argentina
Sampor C:
Hematology-Oncology Service, Hospital de Pediatría JP Garrahan, Buenos Aires, Argentina
Sgroi M:
Ophthalmology Service, Hospital de Pediatría JP Garrahan, Buenos Aires, Argentina
Lagomarsino E:
Pharmacy Service, Hospital de Pediatría JP Garrahan, Buenos Aires, Argentina
Fandiño A:
Ophthalmology Service, Hospital de Pediatría JP Garrahan, Buenos Aires, Argentina
Llera AS:
National Scientific and Technical Research Council, CONICET, Buenos Aires, Argentina
Laboratory of Molecular and Cellular Therapy, Instituto Leloir - Instituto de Investigaciones Bioquímicas de Buenos Aires (IIBBA), Buenos Aires, Argentina
Chantada G:
SJD Pediatric Cancer Center Barcelona, Hospital Sant Joan de Deu, Barcelona, Spain
Institut de Recerca Sant Joan de Déu, Barcelona, Spain
Carcaboso AM:
SJD Pediatric Cancer Center Barcelona, Hospital Sant Joan de Deu, Barcelona, Spain
Institut de Recerca Sant Joan de Déu, Barcelona, Spain
Schaiquevich P:
Unit of Innovative Treatments, Hospital de Pediatría JP Garrahan, Buenos Aires, Argentina
National Scientific and Technical Research Council, CONICET, Buenos Aires, Argentina
Green Submitted, gold
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