Abstract

Platinum compounds cause significant clinical neurotoxicity. Several studies highlight neurological complications especially in paediatric oncology patients with Central Nervous System (CNS) and non-CNS malignancies. To understand the toxicity mechanisms of platinum drugs at cellular and molecular levels in the immature brain, which appears more vulnerable to injury than in the adult one, we compared the effects in vivo of the most used platinum compounds, i.e., cisdichlorodiammineplatinum (cisplatin, cisPt), and the new [Pt(O,O′-acac)(γ-acac)(DMS)] (PtAcacDMS). As models of developing brain areas, we have chosen the cerebellum and hippocampus dentate gyrus. Both areas show the neurogenesis events, from proliferation to differentiation and synaptogenesis, and therefore allow comparing the action of platinum compounds with DNA and non-DNA targets. Here, we focused on the changes in the intracellular calcium homeostasis within CNS architecture, using two immunohistochemical markers, the calcium buffer protein Calbindin and Plasma Membrane Calcium ATPase. From the comparison of the cisPt and PtAcacDMS effects, it emerges how essential the equilibrium and synergy between CB and PMCA1 is or how important the presence of at least one of them is to warrant the morphology and function of nervous tissue and limit neuroarchitecture damages, depending on the peculiar and intrinsic properties of the developing CNS areas.

Highlights

  • The modulation of intracellular calcium is a fundamental factor in the activation of cell death [42]

  • Postnatal brain ontogenesis shows critical and vulnerable windows in which disturbances in calcium homeostasis should allow to dramatic consequences

  • It is known that the favourable advantages and toxic effects of PtAcacDMS on endometrial cancer cells (HeLa) are due to a rapid and sustained apoptotic response characterized by (i) mitochondrial depolarization, (ii) cytosol accumulation of cytochrome c, (iii) translocation from cytosol to mitochondria of some proapototic proteins, (iv) activation of caspase 7 and 9, and v. chromatin condensation and DNA fragmentation [38]

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Summary

Introduction

State of Art on Toxicity of Platinum Compounds and Aim. Platinating compounds have been recognized for over 30 years as anticancer agents used for the treatment of several types of tumors. Its clinical benefits were addressed to testicular, ovarian, cervical head and neck, non-small cell lung, and lymphoma cancers [1,2,3]. Besides cisPt, several platinum compounds were tested in clinical trials: The different platin compounds are used for different types of cancers because each varies in its efficiency for a specific tumor. It has been demonstrated in chemotherapies that cisplatin is superior to carboplatin in treatment of tumor testis, bladder, head and neck, small cell lung cancer and in paediatric malignancies whereas in other cancer types, carboplatin has tended to replace cisplatin. The use of platinum compounds is limited due to toxic side effects in normal tissues

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