Journal Article Ppublish 2 citations
PubMed: 39636723 DOI: 10.1167/iovs.65.14.14
Mimicking Retinoblastoma Treatment With Repeated Topotecan or Melphalan Develops Cross-Resistance to Classic Agents But Not to Repurposed Drugs.
Invest Ophthalmol Vis Sci 65(14):14
Authors: María Belen Cancela, Ursula Winter, Santiago Zugbi, Milagros Dinardi, Daniela Alves da Quinta, Rosario Aschero, Daiana Ganiewich, Claudia Sampor, Mariana Sgroi, Eduardo Lagomarsino, Adriana Fandiño, Andrea S Llera, Guillermo Chantada, Angel M Carcaboso, Paula Schaiquevich
Affiliations
- Unit of Innovative Treatments, Hospital de Pediatría JP Garrahan, Buenos Aires, Argentina.
- 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.
- SJD Pediatric Cancer Center Barcelona, Hospital Sant Joan de Deu, Barcelona, Spain.
- Institut de Recerca Sant Joan de Deu, Barcelona, Spain.
- Hematology-Oncology Service, Hospital de Pediatría JP Garrahan, Buenos Aires, Argentina.
- Ophthalmology Service, Hospital de Pediatría JP Garrahan, Buenos Aires, Argentina.
- Pharmacy Service, Hospital de Pediatría JP Garrahan, Buenos Aires, Argentina.
Abstract
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.
MeSH
Cells, Retinoblastoma, Ophthalmology, Pharmaceutical Preparations, Melphalan, Drug Therapy, Therapeutics, Topotecan, Carboplatin, Chemotherapy