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In vitro and in vivo anticancer effects of two quinoline–platinum(II) complexes on human osteosarcoma models

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Abstract

Platinum-based drugs, mainly cisplatin, are used for the treatment of several solid tumors such as OS. However, cisplatin treatment often results in the development of chemoresistance, leading therapeutic failure. We have previously reported that platinum complexes containing 8-hydroxyquinoline ligands have good antitumor activity against different cancer cell lines and with a different and better cytotoxic profile than cisplatin. Here, the anticancer properties of two different quinoline–platinum complexes [Pt(Cl)2(quinoline)(dmso)] (1) [PtCl(8-O-quinoline)(dmso)] (2) on in vitro (2D and 3D) and in vivo models (xenograft tumor of human osteosarcoma in mice) are presented. In this order, [PtCl(8-O-quinoline)(dmso)] (2) impaired cell viability to have a more pronounced antitumor effect than cisplatin on MG-63 osteosarcoma cells (IC50 4 µM vs. 39 µM). Besides, [PtCl(8-O-quinoline)(dmso)] (2) increased ROS production in a dose-manner response and this compound induced early and late apoptotic fractions of human osteosarcoma cells. Finally, [PtCl(8-O-quinoline)(dmso)] (2) decreased the cell viability of multicellular spheroids and reduced the tumor volume on athymic nude mice N:NIH(S) Fox1nu without inducing side effects. In this way, [PtCl(8-O-quinoline)(dmso)] (2) did not alter the normal cytoarchitecture of liver and kidney and the blood biomarkers (GPT, GOT, uremia, and creatinine) did not suffer modifications. Taken together, our data indicate that these compounds showed a better anticancer performance than cisplatin on in vitro and in vivo studies. These results showed the importance of chelation in the antitumor properties, suggesting that the [PtCl(8-O-quinoline)(dmso)] (2) might be a promising agent for the treatment of human osteosarcoma tumors resistant to cisplatin.

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Acknowledgements

SBE and IEL are members of the Research Carrer, CONICET, Argentina. JFCV and MCR have a fellowship from CONICET and ANPCyT, Argentina, respectively. We also gratefully acknowledge to Dra Ortiz Mayor from Hospital Padilla, Tucuman, Argentina, to help with the Histopathology studies. Moreover, the authors would like to thank MC. Bernal for her careful revision of the manuscript.

Funding

This work was partly supported by UNLP (11X/690), CONICET (PIP 00340), and ANPCyT (PICT 2014-2223) from Argentina and CTQ2015-64561-R from Spain.

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Authors and Affiliations

  1. Chair of Pathologic Biochemistry, Exact School Sciences, National University of La Plata, 1900, La Plata, Argentina

    Maria Carolina Ruiz & Ana Laura Di Virgilio

  2. Inorganic Chemistry Center (CONICET-UNLP) Exact School Sciences, National University of La Plata, 1900, La Plata, Argentina

    Maria Carolina Ruiz, Ana Laura Di Virgilio & Ignacio Esteban León

  3. Lab Experimental Animals, Veterinary School Sciences, National University of La Plata, 1900, La Plata, Argentina

    Agustina Resasco & Miguel Ayala

  4. Chemistry, Biochemistry and Pharmacy Department, Algarve University, 8005-139, Faro, Portugal

    Isabel Cavaco

  5. Inorganic Chemistry Department, Autonomous University of Madrid, 28049, Madrid, Spain

    Silvia Cabrera

  6. Organic Chemistry Department, Universidad Autónoma de Madrid, 28049, Madrid, Spain

    Jose Aleman

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  1. Maria Carolina Ruiz
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  2. Agustina Resasco
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  3. Ana Laura Di Virgilio
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Correspondence to Ignacio Esteban León.

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The animal study was conducted in accordance with the Guide for the Care and Use of Laboratory Animals (National Research Council, USA 2002. Laboratory Animals. A.A Tuffery, 1995. London: John Wiley). All efforts were made to minimize animal suffering, to decrease the number of animals used, and to utilize possible alternatives to in vivo techniques.

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Figure SM1

Effect of cisplatin on the externalization of PS by flow cytometry in MG-63 cells. Cells were incubated with 25, 50 and 100 μM of cisplatin during 6 h (A). Graphical bars show the percentage of Annexin V (+) and Annexin V (+)/ PI (+) cells. Results are expressed as the mean ± SEM, n = 9, *significant differences vs. control (p < 0.01) (B). (C) Effect of complex 2 on the MMP by flow cytometry in MG-63 cells (TIF 276 KB)

Figure SM2

Effects of cisplatin and compound 2 on survival rate. The Kaplan–Meier survival curve (A) Control vs cisplatin (B) Compound 2 vs cisplatin. The figure shows improvement of life span of xenograft-bearing mice treated compound 2 (6 mg/Kg) in comparison with cisplatin (6 mg/Kg) (n = 9 per group). Mice were treated as indicated in Figure 9 and were sacrificed throughout the study period upon reaching our study end point (TIF 74 KB)

Figure SM3

Histopathology of tumor samples. Upper panel male tumor control samples, (A) Arrow, osteoid substance, Arrow-dash, atypical osteocytes cells, Circle, necrosis zone. (B) Tumor coagulative necrosis. Lower panel male tumor treatment samples. (C) Arrow, fibrotic tissue. (D) Circles, apoptotic focuses. Tumor samples were dissected by scalpel and stained with hematoxylin/eosin. Magnifications ×40, and ×100 are indicated (TIF 1161 KB)

Figure SM4

Histopathology of the liver (A, B, D, E) and kidney samples (C, F). Upper panel male liver and kidney control samples, (A) Control liver architecture (B) Control liver Arrow: sinusoids, Dashed arrow: kupffer cells. (C) Control kidney architecture, Arrow: glomeruli, Dash arrow: tubules. Lower panel liver and kidney treatment samples (D) Treatment liver Arrow: microvacuolar (E) Treatment liver Arrow: Councilman hyaline bodies. (F) Treatment kidney, Arrow: glomeruli, Dash arrow: tubules. Samples were stained with hematoxylin/eosin. Magnifications ×40, and ×100 are indicated (TIF 1708 KB)

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Ruiz, M.C., Resasco, A., Di Virgilio, A.L. et al. In vitro and in vivo anticancer effects of two quinoline–platinum(II) complexes on human osteosarcoma models. Cancer Chemother Pharmacol 83, 681–692 (2019). https://doi.org/10.1007/s00280-019-03773-x

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