Purchase this article with an account.
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.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
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.
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.
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).
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.
This PDF is available to Subscribers Only