The Strange Case: The Unsymmetric Cisplatin-Based Pt(IV) Prodrug [Pt(CH3COO)Cl2(NH3)2(OH)] Exhibits Higher Cytotoxic Activity with respect to Its Symmetric Congeners due to Carrier-Mediated Cellular Uptake

Elisabetta Gabano; Ilaria Zanellato; Giulia Pinton; Laura Moro; Mauro Ravera; Domenico Osella

doi:10.1155/2022/3698391

The Strange Case: The Unsymmetric Cisplatin-Based Pt(IV) Prodrug [Pt(CH₃COO)Cl₂(NH₃)₂(OH)] Exhibits Higher Cytotoxic Activity with respect to Its Symmetric Congeners due to Carrier-Mediated Cellular Uptake

Elisabetta Gabano
, Ilaria Zanellato
, Giulia Pinton
, Laura Moro
, Mauro Ravera
, Domenico Osella

Research output: Contribution to journal › Article › peer-review

Abstract

The biological behavior of the axially unsymmetric antitumor prodrug (OC-6-44)-Acetatodiamminedichloridohydroxidoplatinum(IV), 2, was deeply investigated and compared with that of analogous symmetric Pt(IV) complexes, namely, dihydroxido 1 and diacetato 3, which have a similar structure. The complexes were tested on a panel of human tumor cell lines. Complex 2 showed an anomalous higher cytotoxicity (similar to that of cisplatin) with respect to their analogues 1 and 3. Their reduction potentials, reduction kinetics, lipophilicity, and membrane affinity are compared. Cellular uptake and DNA platination of Pt(IV) complexes were deeply investigated in the sensitive A2780 human ovarian cancer cell line and in the corresponding resistant A2780cisR subline. The unexpected activity of 2 appears to be related to its peculiar cellular accumulation and not to a different rate of reduction or a different efficacy in DNA platination and/or efficiency in apoptosis induction. Although the exact mechanism of cell uptake is not fully deciphered, a series of naïve experiments indicates an energy-dependent, carrier-mediated transport: The organic cation transporters (OCTs) are the likely proteins involved.

Original language	English
Article number	3698391
Journal	Bioinorganic Chemistry and Applications
Volume	2022
DOIs	https://doi.org/10.1155/2022/3698391
Publication status	Published - 2022

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Gabano, E., Zanellato, I., Pinton, G., Moro, L., Ravera, M., & Osella, D. (2022). The Strange Case: The Unsymmetric Cisplatin-Based Pt(IV) Prodrug [Pt(CH₃COO)Cl₂(NH₃)₂(OH)] Exhibits Higher Cytotoxic Activity with respect to Its Symmetric Congeners due to Carrier-Mediated Cellular Uptake. Bioinorganic Chemistry and Applications, 2022, Article 3698391. https://doi.org/10.1155/2022/3698391

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title = "The Strange Case: The Unsymmetric Cisplatin-Based Pt(IV) Prodrug [Pt(CH3COO)Cl2(NH3)2(OH)] Exhibits Higher Cytotoxic Activity with respect to Its Symmetric Congeners due to Carrier-Mediated Cellular Uptake",

abstract = "The biological behavior of the axially unsymmetric antitumor prodrug (OC-6-44)-Acetatodiamminedichloridohydroxidoplatinum(IV), 2, was deeply investigated and compared with that of analogous symmetric Pt(IV) complexes, namely, dihydroxido 1 and diacetato 3, which have a similar structure. The complexes were tested on a panel of human tumor cell lines. Complex 2 showed an anomalous higher cytotoxicity (similar to that of cisplatin) with respect to their analogues 1 and 3. Their reduction potentials, reduction kinetics, lipophilicity, and membrane affinity are compared. Cellular uptake and DNA platination of Pt(IV) complexes were deeply investigated in the sensitive A2780 human ovarian cancer cell line and in the corresponding resistant A2780cisR subline. The unexpected activity of 2 appears to be related to its peculiar cellular accumulation and not to a different rate of reduction or a different efficacy in DNA platination and/or efficiency in apoptosis induction. Although the exact mechanism of cell uptake is not fully deciphered, a series of na{\"i}ve experiments indicates an energy-dependent, carrier-mediated transport: The organic cation transporters (OCTs) are the likely proteins involved.",

author = "Elisabetta Gabano and Ilaria Zanellato and Giulia Pinton and Laura Moro and Mauro Ravera and Domenico Osella",

note = "Publisher Copyright: {\textcopyright} 2022 Elisabetta Gabano et al.",

year = "2022",

doi = "10.1155/2022/3698391",

language = "English",

volume = "2022",

journal = "Bioinorganic Chemistry and Applications",

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Gabano, E, Zanellato, I, Pinton, G , Moro, L , Ravera, M & Osella, D 2022, 'The Strange Case: The Unsymmetric Cisplatin-Based Pt(IV) Prodrug [Pt(CH₃COO)Cl₂(NH₃)₂(OH)] Exhibits Higher Cytotoxic Activity with respect to Its Symmetric Congeners due to Carrier-Mediated Cellular Uptake', Bioinorganic Chemistry and Applications, vol. 2022, 3698391. https://doi.org/10.1155/2022/3698391

The Strange Case: The Unsymmetric Cisplatin-Based Pt(IV) Prodrug [Pt(CH₃COO)Cl₂(NH₃)₂(OH)] Exhibits Higher Cytotoxic Activity with respect to Its Symmetric Congeners due to Carrier-Mediated Cellular Uptake. / Gabano, Elisabetta; Zanellato, Ilaria; Pinton, Giulia et al.
In: Bioinorganic Chemistry and Applications, Vol. 2022, 3698391, 2022.

Research output: Contribution to journal › Article › peer-review

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AU - Gabano, Elisabetta

AU - Zanellato, Ilaria

AU - Pinton, Giulia

AU - Moro, Laura

AU - Ravera, Mauro

AU - Osella, Domenico

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N2 - The biological behavior of the axially unsymmetric antitumor prodrug (OC-6-44)-Acetatodiamminedichloridohydroxidoplatinum(IV), 2, was deeply investigated and compared with that of analogous symmetric Pt(IV) complexes, namely, dihydroxido 1 and diacetato 3, which have a similar structure. The complexes were tested on a panel of human tumor cell lines. Complex 2 showed an anomalous higher cytotoxicity (similar to that of cisplatin) with respect to their analogues 1 and 3. Their reduction potentials, reduction kinetics, lipophilicity, and membrane affinity are compared. Cellular uptake and DNA platination of Pt(IV) complexes were deeply investigated in the sensitive A2780 human ovarian cancer cell line and in the corresponding resistant A2780cisR subline. The unexpected activity of 2 appears to be related to its peculiar cellular accumulation and not to a different rate of reduction or a different efficacy in DNA platination and/or efficiency in apoptosis induction. Although the exact mechanism of cell uptake is not fully deciphered, a series of naïve experiments indicates an energy-dependent, carrier-mediated transport: The organic cation transporters (OCTs) are the likely proteins involved.

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