Sensitivity towards the GRP78 inhibitor KP1339/IT-139 is characterized by apoptosis induction via caspase 8 upon disruption of ER homeostasis

Schoenhacker-Alte, Beatrix; Mohr, Thomas; Pirker, Christine; Kryeziu, Kushtrim; Kuhn, Paul‐Steffen; Buck, Alicia; Hofmann, Thilo; Gerner, Christopher; Hermann, Gerrit; Koellensperger, Gunda; Keppler, Bernhard K.; Berger, Walter; Heffeter, Petra

doi:10.1016/j.canlet.2017.07.009

Cited by 47 publications

(52 citation statements)

References 41 publications

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“…Overall, most -omics mass spectrometry-based studies on tumor spheroid analysis rely on extraction The hypothesized difference in the mode of action of the two investigated drugs was reflected by the distinct metabolic shifts, which were observed upon exposing MTSs to the candidate ruthenium drug KP1339. There are indications that this drug is a GRP78 inhibitor, an ER stress sensing chaperone [39,49]. It not only induces ER stress and unfolded protein response, but it has also been shown that it exhibits the hallmarks of immunogenic cell death, calreticulin exposure, and ATP secretion among others [42].…”

Section: Discussionmentioning

confidence: 99%

“…Two drugs of distinctly different proposed modes of action were investigated, namely the clinically established oxaliplatin and the investigational anticancer drug sodium trans-[tetrachloridobis(1H-indazole)ruthenate(III)] (denoted as KP1339). While oxaliplatin exerts its cytotoxic effects through DNA damage and ribosome biogenesis stress [38], there is growing evidence that KP1339 is not a DNA-damaging agent but its primary mode of action is through endoplasmic reticulum stress [39]. Furthermore, KP1339 shows a prodrug nature, as it is thought to be preferentially reduced in the more reductive milieu of solid tumors to the active Ru(II) form.…”

Section: Assessing Metabolic Shifts In Single Mts Exposed To Metal-bamentioning

confidence: 99%

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Single Spheroid Metabolomics: Optimizing Sample Preparation of Three-Dimensional Multicellular Tumor Spheroids

et al. 2019

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Tumor spheroids are important model systems due to the capability of capturing in vivo tumor complexity. In this work, the experimental design of metabolomics workflows using three-dimensional multicellular tumor spheroid (3D MTS) models is addressed. Non-scaffold based cultures of the HCT116 colon carcinoma cell line delivered highly reproducible MTSs with regard to size and other key parameters (such as protein content and fraction of viable cells) as a prerequisite. Carefully optimizing the multiple steps of sample preparation, the developed procedure enabled us to probe the metabolome of single MTSs (diameter range 790 ± 22 µm) in a highly repeatable manner at a considerable throughput. The final protocol consisted of rapid washing of the spheroids on the cultivation plate, followed by cold methanol extraction. 13C enriched internal standards, added upon extraction, were key to obtaining the excellent analytical figures of merit. Targeted metabolomics provided absolute concentrations with average biological repeatabilities of <20% probing MTSs individually. In a proof of principle study, MTSs were exposed to two metal-based anticancer drugs, oxaliplatin and the investigational anticancer drug KP1339 (sodium trans-[tetrachloridobis(1H-indazole)ruthenate(III)]), which exhibit distinctly different modes of action. This difference could be recapitulated in individual metabolic shifts observed from replicate single MTSs. Therefore, biological variation among single spheroids can be assessed using the presented analytical strategy, applicable for in-depth anticancer drug metabolite profiling.

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Section: Discussionmentioning

confidence: 99%

Section: Assessing Metabolic Shifts In Single Mts Exposed To Metal-bamentioning

confidence: 99%

Single Spheroid Metabolomics: Optimizing Sample Preparation of Three-Dimensional Multicellular Tumor Spheroids

et al. 2019

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“…To the best of our knowledge, three Ru(III)-containing compounds entered in clinical trials: NAMI-A [45,46], KP1019 [47][48][49][50][51][52][53], as well as its sodium salt analogue named IT-139, formerly known as NKP-1339 [54][55][56][57][58]. Despite their structural similarities (Figure 1), these complexes dramatically differ in their bioactivity [59].…”

Section: Anticancer Activity and Mechanism Of Action Of The Lead Low mentioning

confidence: 99%

“…In contrast, KP1019 exhibited marked cytotoxic activity in vitro in cisplatin-resistant human colon carcinoma cell lines, as well as significant anti-tumour effects in vivo against a wide variety of tumour xenografts through induction of apoptosis [47][48][49][50][51][52][53]. NKP-1339 is the most recent compound entered in clinical trials against solid cancer forms, showing a manageable safety profile with absence of neurotoxicity and dose-limiting haematological toxicity [54][55][56][57][58].…”

Section: Anticancer Activity and Mechanism Of Action Of The Lead Low mentioning

confidence: 99%

Anticancer Ruthenium(III) Complexes and Ru(III)-Containing Nanoformulations: An Update on the Mechanism of Action and Biological Activity

et al. 2019

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The great advances in the studies on metal complexes for the treatment of different cancer forms, starting from the pioneering works on platinum derivatives, have fostered an increasingly growing interest in their properties and biomedical applications. Among the various metal-containing drugs investigated thus far, ruthenium(III) complexes have emerged for their selective cytotoxic activity in vitro and promising anticancer properties in vivo, also leading to a few candidates in advanced clinical trials. Aiming at addressing the solubility, stability and cellular uptake issues of low molecular weight Ru(III)-based compounds, some research groups have proposed the development of suitable drug delivery systems (e.g., taking advantage of nanoparticles, liposomes, etc.) able to enhance their activity compared to the naked drugs. This review highlights the unique role of Ru(III) complexes in the current panorama of anticancer agents, with particular emphasis on Ru-containing nanoformulations based on the incorporation of the Ru(III) complexes into suitable nanocarriers in order to enhance their bioavailability and pharmacokinetic properties. Preclinical evaluation of these nanoaggregates is discussed with a special focus on the investigation of their mechanism of action at a molecular level, highlighting their pharmacological potential in tumour disease models and value for biomedical applications.

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“…NKP-1339 is active against solid malignancies such as non-small cell lung cancer, colorectal carcinoma and the treatment is accompanied by minor side effects [5,6]. While cisplatin induces DNA damage via adduct formation [7], endoplasmic reticulum stress and reactive oxygen species-related effects were found to be involved in the mechanism of action of NKP-1339 [5,8]. Ru (III) complexes are considered as prodrugs that are activated by reduction and it provides the impetus for the development of various Ru(II) anticancer compounds [5].…”

Section: Imidazolium Trans-[tetrachlorido(dmso)(imidazole)ruthenate(imentioning

confidence: 99%

Comparative solution equilibrium and structural studies of half-sandwich ruthenium(II)(η6-toluene) complexes of picolinate derivatives

Poljarević

Gál

May

et al. 2018

Journal of Inorganic Biochemistry

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Sensitivity towards the GRP78 inhibitor KP1339/IT-139 is characterized by apoptosis induction via caspase 8 upon disruption of ER homeostasis

Cited by 47 publications

References 41 publications

Single Spheroid Metabolomics: Optimizing Sample Preparation of Three-Dimensional Multicellular Tumor Spheroids

Single Spheroid Metabolomics: Optimizing Sample Preparation of Three-Dimensional Multicellular Tumor Spheroids

Anticancer Ruthenium(III) Complexes and Ru(III)-Containing Nanoformulations: An Update on the Mechanism of Action and Biological Activity

Comparative solution equilibrium and structural studies of half-sandwich ruthenium(II)(η6-toluene) complexes of picolinate derivatives

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