The rediscovery of platinum-based cancer therapy

Rottenberg, Sven; Disler, Carmen; Perego, Paola

doi:10.1038/s41568-020-00308-y

Cited by 578 publications

(490 citation statements)

References 142 publications

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“…These changes can be explained the gain of mutations of actively proliferating cells, or by epigenetic changes in the case of quiescent cells, [30,31]. It has been shown that through clonal selection and expansion, a stable resistance is achieved for clones with resistant mutations, or a more transient resistance in nature for cells resistance acquired via epigenetic changes [30,32]. A future study of our model will be designed to investigate the nature of resistance acquisition of our cells and whether it is due to resistant mutations, epigenetic changes, or a combination of both.…”

Section: Discussionmentioning

confidence: 99%

“…Further analysis revealed the expression of Glutathione biosynthesis, recycling and conjugation pathway, and the Gamma glutamyl biosynthesis pathway in HMPOS-2.5R and HMPOS-10R cell line correspondently. These pathways promote the activation of glutathione S transferase (GST) enzyme that hydrolyze the active group of platinum agents and thus mitigate their effect on malignant cells [32,34]. In addition, GST has a critical role in DNA repair, which ultimately promote evasion of apoptosis and cell survival [35,36].…”

Section: Discussionmentioning

confidence: 99%

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Exosomal Proteomic Signatures Correlate With Drug Resistance and Carboplatin Treatment Outcome in a Spontaneous Model of Canine Osteosarcoma

Weinman

Ramsey

Leeper

et al. 2021

Preprint

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BackgroundOsteosarcoma patients often experience poor outcomes despite chemotherapy treatment, likely due in part to various mechanisms of tumor cell innate and/or acquired drug resistance. Exosomes, microvesicles secreted by cells, have been shown to play a role in drug resistance, but a comprehensive protein signature relating to osteosarcoma carboplatin resistance has not been fully characterized. MethodsIn this study, cell lysates and exosomes from two derivatives (HMPOS-2.5R and HMPOS-10R) of the HMPOS osteosarcoma cell line generated by repeated carboplatin treatment and recovery, were characterized proteomically by mass spectrometry. Protein cargos of circulating serum exosomes from dogs with naturally occurring osteosarcoma, were also assessed by mass spectrometry, to identify biomarkers that discriminate between good and poor responders to carboplatin therapy. ResultsBoth cell lysates and exosomes exhibited distinct protein signatures related to drug resistance. Furthermore, exosomes from the resistant HMPOS-2.5R cell line were found to transfer drug resistance to drug-sensitive HMPOS cells. The comparison of serum exosomes from dogs with a favorable disease-free interval [DFI] of >300 days, and dogs with <100 days DFI revealed a proteomic signature that could discriminate between the two cohorts with high accuracy. Furthermore, when the patient’s exosomes were compared to exosomes isolated from carboplatin resistant cell lines, several putative biomarkers were found to be shared. ConclusionsThe findings of this study highlight the significance of exosomes in the potential transfer of drug resistance, and the discovery of novel biomarkers for the development of liquid biopsies to better guide personalized chemotherapy treatment.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Exosomal Proteomic Signatures Correlate With Drug Resistance and Carboplatin Treatment Outcome in a Spontaneous Model of Canine Osteosarcoma

Weinman

Ramsey

Leeper

et al. 2021

Preprint

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“…Cisplatin, the first metallodrug with anticancer activity approved by FDA, entered the clinical practice at the end of the '70s and, despite its severe side effects [1], is currently one of the most widely used drugs in anticancer therapy [2]. In this frame, the numerous adverse reactions associated with the use of cisplatin, prompted the scientific community to study many other Pt-based drugs as antitumor agents and to search for other anticancer compounds based on metals alternative to Pt, such as gold, ruthenium, iridium or arsenic [3].…”

Section: Introductionmentioning

confidence: 99%

Arsenoplatin-Ferritin Nanocage: Structure and Cytotoxicity

Ferraro

Pratesi

Cirri

et al. 2021

IJMS

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Arsenoplatin-1 (AP-1), the prototype of a novel class of metallodrugs containing a PtAs(OH)2 core, was encapsulated within the apoferritin (AFt) nanocage. UV-Vis absorption spectroscopy and inductively coupled plasma-atomic emission spectroscopy measurements confirmed metallodrug encapsulation and allowed us to determine the average amount of AP-1 trapped inside the cage. The X-ray structure of AP-1-encapsulated AFt was solved at 1.50 Å. Diffraction data revealed that an AP-1 fragment coordinates the side chain of a His residue. The biological activity of AP-1-loaded AFt was comparatively tested on a few representative cancer and non-cancer cell lines. Even though the presence of the cage reduces the overall cytotoxicity of AP-1, it improves its selectivity towards cancer cells.

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“…Additionally, chemoresistance mechanisms can arise, reducing the efficacy of these drugs. While mechanisms of resistance have long been established, including DNA damage repair and drug export (Galluzzi et al, 2012), other mechanisms, such as the import of platinum drugs through volume regulated anion channels (VRACs) are more recently discovered and present new opportunities for therapeutic development (Planells-Cases et al, 2015a; Rottenberg et al, 2021). Despite their limitations, platinum-based drugs remain the standard of care in many cancer types and with a paucity of better treatment options for many patients, these drugs will remain in use for the foreseeable future.…”

Section: Introductionmentioning

confidence: 99%

NPEPPS is a novel and druggable driver of platinum resistance

Jones

Goodspeed

Akbarzadeh³

et al. 2021

Preprint

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Platinum-based chemotherapeutics are used in many combination regimens in cancer. Despite extensive use across diverse cancer types, there is room for improved efficacy and patient selection for treatment. Here, we use bladder cancer to address both issues. A multi-omic assessment of five human bladder cancer cell lines and their chemotherapy resistant derivatives, coupled with in vitro whole-genome CRISPR screens were used to define functional drivers of treatment resistance. We identified 46 genes that sensitized the resistant cell lines to cisplatin plus gemcitabine (GemCis), a standard combination therapy in bladder cancer. Most genes were involved with DNA damage and repair pathways, which have previously been associated with enhanced sensitivity to cisplatin. Evaluating expression of the 46 genes in the whole transcriptome and proteome data in parental and resistant lines identified the puromycin sensitive aminopeptidase, NPEPPS, as a novel hit. Depletion of NPEPPS resulted in sensitizing resistant bladder cancer cells to cisplatin in vitro and in xenograft experiments. Pharmacologic inhibition of NPEPPS with tosedostat in cells and in chemoresistant, bladder cancer patient-derived tumoroids improved response to cisplatin. Prior work found NPEPPS in a protein complex with volume regulated anion channels (VRACs) in several cell line models. Interestingly, depletion of two VRAC subunits, LRRC8A and LRRC8D, known importers of intracellular cisplatin, enhanced resistance to cisplatin. Our findings support NPEPPS as a novel and druggable driver of cisplatin resistance with the potential for rapid translation to clinical investigation.

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The rediscovery of platinum-based cancer therapy

Cited by 578 publications

References 142 publications

Exosomal Proteomic Signatures Correlate With Drug Resistance and Carboplatin Treatment Outcome in a Spontaneous Model of Canine Osteosarcoma

Exosomal Proteomic Signatures Correlate With Drug Resistance and Carboplatin Treatment Outcome in a Spontaneous Model of Canine Osteosarcoma

Arsenoplatin-Ferritin Nanocage: Structure and Cytotoxicity

NPEPPS is a novel and druggable driver of platinum resistance

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