Pharmacological Treatment of Chemotherapy-Induced Neuropathic Pain: PPARγ Agonists as a Promising Tool

Quintão, Nara Lins Meira; Santin, José Roberto; Stoeberl, Luis Carlos; Corrêa, Thiago Patrício; Melato, Jéssica; Costa, Robson

doi:10.3389/fnins.2019.00907

Cited by 68 publications

(46 citation statements)

References 151 publications

(165 reference statements)

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“…Substantial evidence indicates that activating PPARγ synergistically enhances the efficacy of CDDP, minimizes its toxicity, and overcomes CDDP resistance (3,5,6,9,10). Furthermore, a PPARγ ligand can decrease the incidence of nephrotoxicity, which is experienced in 30% of CDDPtreated patients, by reducing TNF-α, a crucial player in CDDP-induced nephrotoxicity (11,12).…”

Section: Discussionmentioning

confidence: 99%

PPARγ Agonist Pioglitazone in Combination With Cisplatinum Arrests a Chemotherapy-resistant Osteosarcoma PDOX Model

Higuchi¹,

Yamamoto²,

Sugisawa³

et al. 2019

Cancer Genomics Proteomics

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Background/Aim: Cisplatinum (CDDP) is a firstline drug in osteosarcoma treatment and the acquisition of resistance to CDDP is associated with a poor prognosis. Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear hormone receptor that plays important roles in cell proliferation, differentiation, development, metabolism and cell death. Recently, PPARγ was reported to enhance the efficacy, overcome resistance, and decrease the toxicity of CDDP in various human cancers. In this study we tested whether pioglitazone (PIO), a PPARγ agonist, could overcome CDDP resistance in osteosarcoma. Materials and Methods: In this study, we used a human osteosarcoma cell line and a patient-derived orthotopic xenograft (PDOX) models of osteosarcoma. We measured cell viability of 143B human osteosarcoma cells when treated with CDDP and PIO. We randomized PDOX models of osteosarcoma into four treatment groups: Group 1, Untreated control; Group 2, PIO alone; Group 3, CDDP alone; Group 4, a combination of CDDP and PIO. Each group comprised six mice. Mice were treated for 14 days and tumor size and body weight were measured. Results: Cell viability of 143B human osteosarcoma cells was significantly reduced when PIO (50 μmol/l) was combined with CDDP compared to CDDP alone. PDOX osteosarcoma tumors treated with the CDDP-PIO combination showed the strongest tumor growth inhibition compared to other treatment groups. PDOX osteosarcoma tumors treated with the CDDP-PIO combination had the least cancer cells and the most necrosis in histological section. Conclusion: These results suggest that combining PIO along with CDDP could be an effective treatment strategy for osteosarcoma and has important clinical potential for patients. Cisplatinum (CDDP) is first-line therapy for osteosarcoma. However, its use is limited due to side-effects, such as nephrotoxicity, neuropathies, and/or bone marrow toxicity (1). Peroxisome proliferator-activated receptor gamma (PPARγ) is a member of the nuclear hormone receptor superfamily. PPARγ plays important roles in cell proliferation and differentiation, lipid metabolism, development, and cell death and is a candidate tumor suppressor gene (2). PPARγ ligands exert anti-tumor efficacy in various cancer models, however, monotherapy of PPARγ ligands showed a limited efficacy in clinical trials (3). Even though PPARγ ligands are less efficacious as monotherapy, in combination with traditional chemotherapy drugs, they showed improved clinical potential (3). We previously showed that the PPARγ ligand pioglitazone (PIO) could overcome doxorubicin-resistance in an osteosarcoma patient-derived orthotopic xenograft (PDOX) model (4). It has been demonstrated that PPARγ ligands combined with platinum-based drugs increase therapeutic efficacy in multiple cancer models such as nonsmall cell lung cancer (5), colon cancer (6), and ovarian cancer (6), but not in osteosarcoma. In the present study, we tested whether PIO could overcome CDDP-resistance in osteosarcoma PDOX model.

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Section: Discussionmentioning

confidence: 99%

PPARγ Agonist Pioglitazone in Combination With Cisplatinum Arrests a Chemotherapy-resistant Osteosarcoma PDOX Model

Higuchi¹,

Yamamoto²,

Sugisawa³

et al. 2019

Cancer Genomics Proteomics

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“…However, most of the studies regarding the central effects of neurotoxic chemotherapy are only focused on cognitive impairment ("chemofog" or "chemobrain") [61][62][63], while very little attention has been paid so far to this important aspect, particularly regarding the painful component of OIPN. It is, therefore, advisable that this lack of information will be addressed by well-conducted clinical studies profiting from the possibility to investigate the central nervous system at the functional level with magnetic resonance imaging or to modulate its activity using transcranial stimulation because this approach might open the way to new therapeutic attempts [64].…”

Section: Discussionmentioning

confidence: 99%

Management of Oxaliplatin-Induced Peripheral Sensory Neuropathy

Cavaletti

Marmiroli

2020

Cancers

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Oxaliplatin-induced peripheral neurotoxicity (OIPN) is a severe and potentially permanent side effect of cancer treatment affecting the majority of oxaliplatin-treated patients, mostly with the onset of acute symptoms, but also with the establishment of a chronic sensory loss that is supposed to be due to dorsal root ganglia neuron damage. The pathogenesis of acute as well as chronic OIPN is still not completely known, and this is a limitation in the identification of effective strategies to prevent or limit their occurrence. Despite intense investigation at the preclinical and clinical levels, no treatment can be suggested for the prevention of OIPN, and only limited evidence for the efficacy of duloxetine in the treatment setting has been provided. In this review, ongoing neuroprotection clinical trials in oxaliplatin-treated patients will be analyzed with particular attention paid to the hypothesis leading to the study, to the trial strengths and weaknesses, and to the outcome measures proposed to test the efficacy of the therapeutic approach. It can be concluded that (1) prevention and treatment of OIPN still remains an important and unmet clinical need, (2) further, high-quality research is mandatory in order to achieve reliable and effective results, and (3) dose and schedule modification of OHP-based chemotherapy is currently the most effective approach to limit the severity of OIPN.

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“…The lattermost category included DMAQ-B1, an insulin mimetic purified from Pseudomassaria sp. [24]; CD437, an activator of retinoic acid receptor-β and -γ [25]; oxaliplatin and carboplatin, FDA approved platinum complexes for the treatment of cancer [26,27]; and PSB-069, a nucleoside triphosphate diphosphohydrolase inhibitor [28] (Fig. 1a).…”

Section: Introductionmentioning

confidence: 99%

Repurposing bioactive compounds for treating multidrug-resistant pathogens

Hummell

Kirienko

2020

Journal of Medical Microbiology

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Introduction. Antimicrobial development is being outpaced by the rising rate of antimicrobial resistance in the developing and industrialized world. Drug repurposing, where novel antibacterial functions can be found for known molecular entities, reduces drug development costs, reduces regulatory hurdles, and increases rate of success. Aim. We sought to characterize the antimicrobial properties of five known bioactives (DMAQ-B1, carboplatin, oxaliplatin, CD437 and PSB-069) that were discovered in a high-throughput phenotypic screen for hits that extend Caenorhabditis elegans survival during exposure to Pseudomonas aeruginosa PA14. Methodology. c.f.u. assays, biofilm staining and fluorescence microscopy were used to assay the compounds' effect on various virulence determinants. Checkerboard assays were used to assess synergy between compounds and conventional antimicrobials. C. elegans-based assays were used to test whether the compounds could also rescue against Enterococcus faecalis and Staphyloccus aureus. Finally, toxicity was assessed in C. elegans and mammalian cells. Results. Four of the compounds rescued C. elegans from a second bacterial pathogen and two of them (DMAQ-B1, a naturally occurring insulin mimetic, and CD437, an agonist of the retinoic acid receptor) rescued against all three. The platinum complexes displayed increased antimicrobial activity against P. aeruginosa . Of the molecules tested, only CD437 showed slight synergy with ampicillin. The two most effective compounds, DMAQ-B1 and CD437, showed toxicity to mammalian cells. Conclusion. Although these compounds' potential for repurposing is limited by their toxicity, our results contribute to this growing field and provide a simple road map for using C. elegans for preliminary testing of known bioactive compounds with predicted antimicrobial activity.

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Pharmacological Treatment of Chemotherapy-Induced Neuropathic Pain: PPARγ Agonists as a Promising Tool

Cited by 68 publications

References 151 publications

PPARγ Agonist Pioglitazone in Combination With Cisplatinum Arrests a Chemotherapy-resistant Osteosarcoma PDOX Model

PPARγ Agonist Pioglitazone in Combination With Cisplatinum Arrests a Chemotherapy-resistant Osteosarcoma PDOX Model

Management of Oxaliplatin-Induced Peripheral Sensory Neuropathy

Repurposing bioactive compounds for treating multidrug-resistant pathogens

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