Drosophila strain specific response to cisplatin neurotoxicity

Abstract

Drosophila melanogaster has recently been developed as a simple, in vivo, genetic model of chemotherapy-induced peripheral neuropathy. Flies treated with the chemotherapy agent cisplatin display both a neurodegenerative phenotype and cell death in rapidly dividing follicles, mimicking the cell specific responses seen in humans. Cisplatin induces climbing deficiencies and loss of fertility in a dose dependent manner. Drosophila sensitivity to cisplatin in both cell types is affected by genetic background. We show that mutation or RNAi-based knockdown of genes known to be associated with CIPN incidence in humans affect sensitivity of flies to CIPN. Drosophila is a promising model with which to study the effect of genetics on sensitivity to CIPN. ARTICLE HISTORY

Analyzing chemotherapy-induced peripheral neuropathy in vivo using non-mammalian animal models

“…For instance, CIPN phenotypes comparable to other neuropathies have been observed in all species regardless of how the chemotherapeutic agent was administered and at which dose (Cavaletti et al, 2000;Cavaletti et al, 1995). Differences in the severity of phenotypes arose, however, these were mostly background-dependent, as shown in mice (Smith et al, 2004) and Drosophila treated with paclitaxel and cisplatin (Groen et al, 2018), respectively.…”

“…Another study tested the role of genetic background in cisplatin neurotoxicity given that humans as well as rodents respond to cisplatin in varying degrees (Groen et al, 2018). Using a negative geotactic climbing assay, the authors found a significantly different backgroundspecific response to cisplatin treatment in various wild type Drosophila strains tested.…”

Cellular Pathogenesis of Chemotherapy-Induced Peripheral Neuropathy: Insights From Drosophila and Human-Engineered Skin Models

“…An additional manual search revealed another article in cisplatin-induced peripheral neuropathy (93). Overall, Drosophila CIPN studies focused on three common chemotherapeutics, paclitaxel (42,43,72,94), cisplatin (66,67,70,71,92), and bortezomib (69). Three of these studies (42,69,72) used Drosophila as a part of multi-model studies.…”

“…A series of studies from the Windebank lab have pioneered Drosophila larval and adult models of cisplatin-induced peripheral neuropathy (66,67,70,71,93). The initial study in the lab used adult fly model to study the effect of cisplatin in neurons in the central nervous system and geotactic climbing behavior (93).…”

“…To understand intercellular mechanisms, in vivo models or in vitro models that allow manipulation and monitoring of multiple cell types are required. Several recent CIPN studies have demonstrated Drosophila melanogaster as a simple and genetically tractable in vivo model that could fill knowledge gaps with conserved CIPN phenotypes and examples with successful translation to other mammalian models (42,43,(66)(67)(68)(69)(70)(71)(72). Utilizing full advantages of Drosophila models as a part of multi-model approaches with physiologically relevant vertebrate models, such as rodent models or human engineered skin models, may provide significant insights into a deeper understanding of CIPN pathology.…”