Metformin restores cisplatin cytotoxicity reduced by allantoin in CML <em>in vitro</em>

Paz,Grazielle Silva; De Amorim,Gisele Cardoso; Fernandes,Janaina

doi:10.3892/wasj.2021.116

Metformin restores cisplatin cytotoxicity reduced by allantoin in CML in vitro

Authors:
- Grazielle Silva Paz
- Gisele Cardoso De Amorim
- Janaina Fernandes
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Affiliations: NUMPEX‑BIO, Duque de Caxias Campus, Federal University of Rio de Janeiro, Duque de Caxias, Rio de Janeiro 25245‑390, Brazil
Published online on: July 15, 2021 https://doi.org/10.3892/wasj.2021.116
Article Number: 45
Copyright: © Paz et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Tumor lysis syndrome (TLS) is a metabolic disorder that mainly affects patients with malignant hematological neoplasms, and its development is frequently related to uric acid accumulation (hyperuricemia). Rasburicase is a recombinant urate oxidase enzyme applied to treat and avoid TLS converting urate into allantoin, a compound easily eliminated by the kidneys. However, a recent study by the authors demonstrated in vitro that an elevated allantoin generation, which has been observed in oncological patients treated with rasburicase, reduced cisplatin cytotoxicity in a non‑small cell lung cancer cell line (H460). Thus, it is necessary to determine the effects of the concomitant use of cisplatin and rasburicase for the treatment of patients with chronic myeloid leukemia (CML); due to the higher incidence of tumor lysis syndrome among patients with CML, it is necessary to search for adjuvant agents that can restore cisplatin cytotoxicity. Among adjuvant agents, metformin is of interest as it is effective, safe and has established pharmacological parameters. Thus, the present study evaluated the capacity of metformin to restore allantoin‑reduced cisplatin cytotoxicity in a CML cell line (K562) in vitro. The cells were treated with metformin (0.1, 0.25, 0.5, 0.6025, 2, 2.5 and 3 mM), cisplatin (15, 16.5, 20, 30 and 33 µM), allantoin (100 and 200 µg/ml), or their combinations for 48 h. Cell viability, cell cycle, morphological analysis and nuclear magnetic resonance experiments were performed. The results revealed that allantoin reduced cisplatin cytotoxicity in the K562 cell line. Thus, metformin synergistically increased cisplatin‑induced cell death and restored the cisplatin cytotoxicity that was reduced by allantoin.

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