June 2020
Volume 61, Issue 7
Free
ARVO Annual Meeting Abstract  |   June 2020
Drug repurposing to circumvent pharmacological resistance in retinoblastoma
Author Affiliations & Notes
  • Paula Schaiquevich
    Hospital de Pediatria JP Garrahan, Buenos Aires, Argentina
  • Ursula Winter
    Hospital de Pediatria JP Garrahan, Buenos Aires, Argentina
  • Maria Belen Cancela
    Hospital de Pediatria JP Garrahan, Buenos Aires, Argentina
  • Santiago Zugbi
    Hospital de Pediatria JP Garrahan, Buenos Aires, Argentina
  • Guillem Pascual Pasto
    Hospital Sant Joan de Deu, Barcelona, Spain
  • Claudia Sampor
    Hospital de Pediatria JP Garrahan, Buenos Aires, Argentina
  • Mariana Sgroi
    Hospital de Pediatria JP Garrahan, Buenos Aires, Argentina
  • Adriana Fandiño
    Hospital de Pediatria JP Garrahan, Buenos Aires, Argentina
  • Guillermo Chantada
    Hospital de Pediatria JP Garrahan, Buenos Aires, Argentina
  • Angel Montero Carcaboso
    Hospital Sant Joan de Deu, Barcelona, Spain
  • Footnotes
    Commercial Relationships   Paula Schaiquevich, None; Ursula Winter, None; Maria Cancela, None; Santiago Zugbi, None; Guillem Pascual Pasto, None; Claudia Sampor, None; Mariana Sgroi, None; Adriana Fandiño, None; Guillermo Chantada, None; Angel Montero Carcaboso, None
  • Footnotes
    Support  Agencia Nacional de Promocion Cientifica y Tecnologica, PICT 2016-1505
Investigative Ophthalmology & Visual Science June 2020, Vol.61, 2818. doi:
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    • Get Citation

      Paula Schaiquevich, Ursula Winter, Maria Belen Cancela, Santiago Zugbi, Guillem Pascual Pasto, Claudia Sampor, Mariana Sgroi, Adriana Fandiño, Guillermo Chantada, Angel Montero Carcaboso; Drug repurposing to circumvent pharmacological resistance in retinoblastoma. Invest. Ophthalmol. Vis. Sci. 2020;61(7):2818.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Scarce information is available on pharmacological resistance in retinoblastoma with potential implications in the pharmacological treatment. Thus, we aimed to establish resistant-cells subtypes to topotecan, melphalan or carboplatin from primary cell cultures, and to study the degree of resistance and cross-resistance among compounds. We also evaluated the use of digoxin drug to circumvent acquired pharmacological resistance.

Methods : Primary cell cultures were obtained after mechanical disaggregation of fresh tumor samples of two upfront enucleated patients with intraocular retinoblastoma, and named as HPG-RBT-12L and HSJD-RB-7. The parental cell lines (HPG-RBT-12L and HSJD-RB-7) were exposed to three weekly doses of topotecan, melphalan or caboplatin at the IC50 of each drug (concentration that inhibits 50% of cell proliferation) previously determined using the MTT assay. Then, the IC50s were determined in the topotecan-resistant (HPG-12L-RT and HSJD-7-RT), melpahlan-resistant (HPG-12L-RM and HSJD-7-RM), and carboplatin-resistant subtypes (HPG-12L-RC and HSJD-7-RC) to verify resistance and to test for possible cross-resistance. Digoxin IC50 was assessed in all parental and resistant-cell subtypes.

Results : Mean topotecan IC50 in HPG-12L-RT and HSJD-7-RT was 7-fold and 5-fold higher than topotecan IC50 in HPG-RBT-12L and HSJD-RB-7, respectively (p<0.05). Mean melphalan IC50 in HPG-12L-RM and HSJD-7-RM was 4-fold higher than melphalan IC50 in HPG-RBT-12L and HSJD-RB-7 (p<0.05). Also, mean carboplatin IC50 in HPG-12L-RC and HSJD-7-RC was 2-fold higher than carboplatin IC50 determined in the corresponding parental cell lines (p<0.05). In all resistant-cell subtypes the IC50 of those drugs to which they had not been previously exposed e.g. were statistically higher than those in the parental cell lines confirming the pharmacological cross-resistance (p<0.05). In all cases, both parental and resistant cells showed similar digoxin IC50s (p>0.05).

Conclusions : We were able to establish primary retinoblastoma cells cultures and the resistant subtypes to topotecan, melphalan or carboplatin. Acquisition of pharmacological resistance involved a 2-to-7 fold increase in the IC50 of each evaluated drug with potential implications in clinical response. Also, digoxin administration is suggested as a drug repositioning candidate to circumvent pharmacological resistance to commonly used chemotherapy in retinoblastoma.

This is a 2020 ARVO Annual Meeting abstract.

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