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ORIGINAL RESEARCH article
Front. Oncol.
Sec. Cancer Molecular Targets and Therapeutics
Volume 15 - 2025 | doi: 10.3389/fonc.2025.1399956
Combination of MLo-1508 with Sunitinib for the experimental treatment of papillary Renal Cell Carcinoma
Provisionally accepted
Ângela Marques-Magalhães 1
Filipa Moreira-Silva 1 Inês Graça 1 Paula C. Dias 2 Margareta P. Correira 1
Maria Ana Alzamora 2 Rui Henrique 1 Marie Lopez 3 Paola B. Armando 4
Vera Miranda-Gonçalves 1
Carmen Jeronimo 5*- 1 IPO-Porto Research Centre, Portuguese Oncology Institute, Porto, Porto, Portugal
- 2 Portuguese Oncology Institute, Porto, Portugal
- 3 UMR5247 Institut des Biomolécules Max Mousseron (IBMM), Montpellier, Languedoc-Roussillon, France
- 4 CNRS – UMR3523 Epigenetic Chemical Biology, Institut Pasteur, France, France
- 5 Research Center, IPO-Porto Research Centre, Portuguese Oncology Institute, Porto, Portugal
Renal cell carcinoma (RCC) is the 14 th most incident cancer worldwide, and no curative therapeutic options are available for advanced and metastatic disease. Hence, new treatment alternatives are urgently needed to tackle disease management and drug resistance. Herein, we explored the use of MLo-1508 as an anti-tumoral agent in RCC and further assessed its combination with sunitinib for the treatment of papillary RCC. We found that MLo-1508 significantly decreased RCC cell viability while inducing apoptosis in a dose-dependent manner without cytotoxicity for non-malignant cells. Moreover, the treatment induced morphometric alterations and DNA damage in all RCC cell lines. MLo-1508 decreased DNMT1 and DNMT3A transcript levels in 786-O and ACHN cells, inhibited DNMT3A activity, and reduced the global DNA methylation content of ACHN cells. When combined with sunitinib, a reduction in ACHN cell viability, as well as cell cycle arrest at G2/M was observed. Importantly, MLo-1508 decreased the sunitinib effective anti-tumoral concentration against ACHN cell viability. In an in vivo ACHN CAM model, the combination induced cell necrosis. Thus, MLo-1508 might improve sensitivity to sunitinib treatment by decreasing the required concentration and delaying resistance acquisition.
Keywords: Renal cell carcinoma, epigenetics, DNA Methylation, MLo-1508, Sunitinib
Received: 12 Mar 2024; Accepted: 03 Mar 2025.
Copyright: © 2025 Marques-Magalhães, Moreira-Silva, Graça, Dias, Correira, Alzamora, Henrique, Lopez, Armando, Miranda-Gonçalves and Jeronimo. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Carmen Jeronimo, Research Center, IPO-Porto Research Centre, Portuguese Oncology Institute, Porto, 4200-072 Porto, Portugal
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