A novel derivative (GTN024) from a natural product, komaroviquinone, induced the apoptosis of high-risk myeloma cells via reactive oxygen production and ER stress

Okayama, Masanobu; Kitabatake, Shotaro; Sato, Mariko; Fujimori, Kota; Ichikawa, Daiju; Matsushita, Maiko; Suto, Yutaka; Iwasaki, Genji; Yamada, Taketo; Kiuchi, Fumiyuki; Hirao, Maki; Kunieda, Hisako; Osada, Makoto; Okamoto, Shinichiro; Hattori, Yutaka

doi:10.1016/j.bbrc.2018.09.177

Cited by 4 publications

(8 citation statements)

References 36 publications

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“…The production of ROS, which is a major anti‐myeloma activity of GTN024, 18 is not the only antiproliferative mechanism of GTN057; we observed herein that GTN057 inhibited HGF receptor/c‐Met in addition to the downstream signaling mediated by ERK1/2, STAT3, and AKT1. The exact molecular mechanisms underlying the inhibition of c‐Met by GTN057 are not yet known.…”

Section: Discussionmentioning

confidence: 69%

“…13,14 In our previous study, KQN and its derivative GTN024 produced ROS in MM cells, which was suspected to be the antitumor mechanism of this derivative. 17,18 We thus investigated whether GTN057 can also produce ROS and induce ROS-dependent MM cell death in the present study, and we observed that GTN057 also produced ROS in MM cells (Figure S1). However, the MM cells' growth inhibition and apoptosis induced by GTN057 were not significantly abrogated by co-culturing with anti-oxidants (Figure S1).…”

Section: Gtn057's Production Of Rosmentioning

confidence: 87%

“… 13 , 17 We reported that GTN024 effectively induced myeloma cell‐death; however, the toxicity of GTN024 to normal hematopoietic cells was of serious concern. 18 It was reported that GTN057 did not inhibit the colony formation of bone marrow cells from mice. 17 As described in the Results section, when mice were injected with 100 mg/kg of GTN057 on 2 days of each 3‐day period over a 2‐week period, no significant neutropenia or systemic toxicity was observed, indicating the low toxicity of this compound.…”

Section: Discussionmentioning

confidence: 98%

“…GTN024 also induced apoptosis in MM cells in vivo by producing ROS. 18 However, GTN024 exhibited significant hematological toxicity in vitro, which hampers the clinical applications of this compound. 17 To identify less‐toxic compounds, we continued our screening of the KQN‐derivatives library and observed that the KQN derivative GTN057 has an anti‐myeloma effect with negligible hematological toxicity in a colony assay (compound 18 in ref.…”

Section: Introductionmentioning

confidence: 99%

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GTN057, a komaroviquinone derivative, induced myeloma cells' death in vivo and inhibited c‐MET tyrosine kinase

et al. 2023

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Objective Despite the development of newly developed drugs, most multiple myeloma (MM) patients with high‐risk cytogenetic abnormalities such as t(4;14) or del17p relapse at anin early stage of their clinical course. We previously reported that a natural product,komaroviquinone (KQN), isolated from the perennial semi‐shrub Dracocephalum komarovi , i.e., komaroviquinone (KQN) and its derivative GTN024 induced the apoptosis of MM cells by producing reactive oxygen species (ROS), but both exhibited significant hematological toxicity. Aim of this study is to clarify anti‐tumor activity, safety and pharmacokinetics of GTN057, an optimization compound of KQN in vivo. Methods ICR/SCID xenograft model of KMS11, a t(4;14) translocation‐positive MM cell line, was used for in vivo study. Mice pharmacokinetics of GTN057 and the degradation products were analyzed by LC‐MS/MS. Results Herein, our in vitro experiments revealed that GTN057 is much less toxic to normal hematopoietic cells, induced the apoptosis of both MM cell lines andpatient samples, including those with high‐risk cytogenetic changes. A xenograft model of a high‐risk MM cell line demonstrated that GTN057 significantly delayed the tumor growth with no apparent hematological or systemic toxicities in vivo. The pathological examination of GTN057‐treated tumors in vivoshowed revealed apoptosis of MM cells and anti‐angiogenesis. In addition to the production of ROS, GTN057 inhibited the downstream signaling of c‐MET, a receptor tyrosine kinase a receptor forand hepatocyte growth factor (HGF) receptor. Thus, GTN057 is less toxic and is able tomay be a candidate drug for treating MM patients, via multifunctional mechanisms. We have also extensively studied the pharmacologyical analysis of GTN057. The metabolites of GTN057, (e.g.,such as GTN054), may also have anti‐tumorantitumor activity. Conclusion Natural products or and their derivatives can could be good sources of antineoplastic drugs even for high‐risk cancer.

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Section: Discussionmentioning

confidence: 69%

Section: Gtn057's Production Of Rosmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

GTN057, a komaroviquinone derivative, induced myeloma cells' death in vivo and inhibited c‐MET tyrosine kinase

et al. 2023

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“…While great strides have been made in the treatment of cancer in recent decades, we still face many open challenges to existing cancer therapies, such as adaptive resistance [4]. Throughout the development of human society, the importance of natural products [4][5][6][7][8][9] and their derivatives [10][11][12] in cancer treatment or prevention is supported by abundant evidence from cancer research [3,13,14], and give hopes to cancer patients.…”

Section: Introductionmentioning

confidence: 99%

Multifloroside Suppressing Proliferation and Colony Formation, Inducing S Cell Cycle Arrest, ROS Production, and Increasing MMP in Human Epidermoid Carcinoma Cell Lines A431

Zhang

Feng

et al. 2019

Molecules

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Multifloroside (4), together with 10-hydroxyoleoside 11-methyl ester (1), 10-hydroxyoleoside dimethyl ester (2), and 10-hydroxyligustroside (3), are all secoiridoids, which are naturally occurring compounds that possess a wide range of biological and pharmacological activities. However, the anti-cancer activity of 1-4 has not been evaluated yet. The objective of this work was to study the anti-cancer activities of 1-4 in the human epidermoid carcinoma cell lines A431 and the human non-small cell lung cancer (NSCLC) cell lines A549. The results indicate that 1-4 differ in potency in their ability to inhibit the proliferation of human A431 and A549 cells, and multifloroside (4) display the highest inhibitory activity against A431 cells. The structure-activity relationships suggest that the o-hydroxy-p-hydroxy-phenylethyl group may contribute to the anti-cancer activity against A431 cells. Multifloroside treatment can also inhibit cell colony formation, arrest the cell cycle in the S-phase, increase the levels of reactive-oxygen-species (ROS), and mitochondrial membrane potential (MMP), but it did not significantly induce cell apoptosis at low concentrations. The findings indicated that multifloroside (4) has the tendency to show selective anti-cancer effects in A431 cells, along with suppressing the colony formation, inducing S cell cycle arrest, ROS production, and increasing MMP.

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Identification of neomacrophorins isolated from Trichoderma sp. 1212-03 as proteasome inhibitors

Uesugi

Honmura

Nishiyama

et al. 2019

Bioorganic & Medicinal Chemistry

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A novel derivative (GTN024) from a natural product, komaroviquinone, induced the apoptosis of high-risk myeloma cells via reactive oxygen production and ER stress

Cited by 4 publications

References 36 publications

GTN057, a komaroviquinone derivative, induced myeloma cells' death in vivo and inhibited c‐MET tyrosine kinase

GTN057, a komaroviquinone derivative, induced myeloma cells' death in vivo and inhibited c‐MET tyrosine kinase

Multifloroside Suppressing Proliferation and Colony Formation, Inducing S Cell Cycle Arrest, ROS Production, and Increasing MMP in Human Epidermoid Carcinoma Cell Lines A431

Identification of neomacrophorins isolated from Trichoderma sp. 1212-03 as proteasome inhibitors

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