Comparative Gene Expression Analysis in WM164 Melanoma Cells Revealed That β-β-Dimethylacrylshikonin Leads to ROS Generation, Loss of Mitochondrial Membrane Potential, and Autophagy Induction

Kretschmer, Nadine; Deutsch, Alexander; Durchschein, Christin; Rinner, Beate; Stallinger, Alexander; Higareda‐Almaraz, Juan Carlos; Scheideler, Marcel; Lohberger, Birgit; Bauer, Rudolf

doi:10.3390/molecules23112823

Cited by 18 publications

(14 citation statements)

References 48 publications

(69 reference statements)

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“…Of relevance to melanoma, DO-SHI has been found to induce apoptosis in B16-F10, 15 and β,β-SHI is reported to trigger apoptosis in the human melanoma WM164 cell line. 1 Based on the limited understanding of DO-SHI and β,β-SHI and the promising data from our recent study, we believe that SHI, DO-SHI, and β,β-SHI offer potential novel interventions for melanoma. Data from the Alamar blue assay indicate that SHI, DO-SHI, and β,β-SHI inhibit A375, B16-F0, and B16-F10 cell viability in a dose-dependent manner.…”

Section: Discussionmentioning

confidence: 91%

“…Despite accounting for about 4% of all skin cancer cases, invasive melanoma contributes to more than 79% of all skin cancer deaths. 1 The cost of treating skin cancer differs according to the stage of the disease as well as the country in which the treatment is received. 2 The average cost of treating melanoma is estimated at USD 3.3 billion annually in the United States.…”

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confidence: 99%

“…For β,β-SHI, Kretschmer et al 16 reported that it regulates ROS generation and mitochondrial membrane potential inducing autophagy in WM164 melanoma cells. 1,16 More recently, the effects of β,β-SHI have been investigated in MUG-Mel1, MUG-Mel2, Sbcl2, WM164 and WM793 melanoma cells, 17 bone tumor, 18 and neuroendocrine tumor 19 cells. However, the effect of β,β-SHI on A375 cell lines is not known.…”

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confidence: 99%

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Investigating the Effects of Shikonin, Deoxyshikonin, and (β,β-Dimethylacryl)Shikonin on Melanoma Cell Lines

Upton

Leavesley

et al. 2020

Natural Product Communications

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Melanoma is the most lethal form of various skin cancers and contributes to more than 79% of all skin cancer deaths. Although there are numerous therapies available for melanoma, the high rate of recurrence in melanoma post-therapy remains a challenging issue for both patients and clinicians. Apoptosis is one of the foundations for cancer treatment as deficient apoptosis is one of the most essential reasons for the formation of tumour tissues. Shikonin (SHI), an active component extracted from Lithospermum erythrorhizon, has been broadly demonstrated to possess antitumorigenic property due to its apoptosis-inducing ability in various cancer cell lines. The analogs of SHI, such as deoxyshikonin (DO-SHI) and (β,β-dimethylacryl)shikonin (β,β-SHI), have also been found to possess similar bioactivities. The apoptosis-inducing ability of SHI and its analogs enable them to be potential anticancer therapies. In this study reported herein, we investigated the effects of SHI, DO-SHI, and β,β-SHI on both human (A375) and mouse (B16-F0 and B16-F10) melanoma cell lines. Cell viability was measured using Alamar blue assay, while cell migration was detected using scratch assay. Cell apoptosis was captured using terminal deoxynucleotidyl dUTP nick end labeling and fluorescence activated cell sorting. Signaling pathway activation was detected using Western blotting. Our results revealed that SHI, DO-SHI, and β,β-SHI reduce cell viability, inhibit cell migration, and induce apoptosis in melanoma cell lines. These 3 molecules-induced apoptosis in A375 is regulated via mitogen-activated protein kinase/caspase 3 signaling pathway. In particular, DO-SHI and β,β-SHI induce higher apoptosis rate in A375 and B16-F0 compared to SHI. The data from this study demonstrate that DO-SHI and β,β-SHI offer potential new reagents for managing melanoma.

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Section: Discussionmentioning

confidence: 91%

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confidence: 99%

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Investigating the Effects of Shikonin, Deoxyshikonin, and (β,β-Dimethylacryl)Shikonin on Melanoma Cell Lines

Upton

Leavesley

et al. 2020

Natural Product Communications

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“…In this line, natto freeze-drying extract and natto water extract, isolated from natto, soybeans fermented by Bacillus subtilis natto , were considered to play a critical role in melanoma cell death through ROS adjustment, autophagy regulation and apoptosis promotion [ 129 ]. In addition, dimethylacrylshikonin, isolated from the roots of Onosma paniculata (Boraginaceae), induced apoptosis, autophagy, ROS generation and loss of mitochondrial membrane potential in WM164 cell line [ 130 ].…”

Section: Melanoma Cell Death and Survival: Simultaneous Regulation Of Oxidative Stress System And Autophagy Machinerymentioning

confidence: 99%

Oxidative Stress and Autophagy as Key Targets in Melanoma Cell Fate

Catalani

Giovarelli

Zecchini

et al. 2021

Cancers

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Melanoma originates from the malignant transformation of melanocytes and is one of the most aggressive forms of cancer. The recent approval of several drugs has increased the chance of survival although a significant subset of patients with metastatic melanoma do not show a long-lasting response to these treatments. The complex cross-talk between oxidative stress and the catabolic process autophagy seems to play a central role in all aspects of melanoma pathophysiology, from initiation to progression and metastasis, including drug resistance. However, determining the fine role of autophagy in cancer death and in response to redox disruption is still a fundamental challenge in order to advance both basic and translational aspects of this field. In order to summarize the interactions among reactive oxygen and nitrogen species, autophagy machinery and proliferation/growth/death/apoptosis/survival, we provide here a narrative review of the preclinical evidence for drugs/treatments that modulate oxidative stress and autophagy in melanoma cells. The significance and the potential for pharmacological targeting (also through multiple and combination approaches) of these two different events, which can contribute independently or simultaneously to the fate of melanoma, may help to define new processes and their interconnections underlying skin cancer biology and unravel new reliable approaches.

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“…In previous studies, we could show that β,β-dimethylacrylshikonin ( 2 ) was the most cytotoxic compound isolated from the roots of O. paniculata and exhibited the strongest cytotoxicity toward several melanoma cell lines [ 13 , 14 ]. Ongoing studies revealed that 2 favored catabolic processes and caused generation of reactive oxygen species, loss of mitochondrial membrane potential, and the upregulation of NOXA expression [ 15 , 16 ]. Finally, this led to apoptosis, autophagy, and cell cycle arrest.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Pharmacological In Vitro Investigations of Novel Shikonin Derivatives with a Special Focus on Cyclopropane Bearing Derivatives

Kretschmer

Hüfner

Durchschein

et al. 2021

IJMS

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Melanoma is the deadliest form of skin cancer and accounts for about three quarters of all skin cancer deaths. Especially at an advanced stage, its treatment is challenging, and survival rates are very low. In previous studies, we showed that the constituents of the roots of Onosma paniculata as well as a synthetic derivative of the most active constituent showed promising results in metastatic melanoma cell lines. In the current study, we address the question whether we can generate further derivatives with optimized activity by synthesis. Therefore, we prepared 31, mainly novel shikonin derivatives and screened them in different melanoma cell lines (WM9, WM164, and MUG-Mel2 cells) using the XTT viability assay. We identified (R)-1-(1,4-dihydro-5,8-dihydroxy-1,4-dioxonaphthalen-2-yl)-4-methylpent-3-enyl 2-cyclopropyl-2-oxoacetate as a novel derivative with even higher activity. Furthermore, pharmacological investigations including the ApoToxGloTM Triplex assay, LDH assay, and cell cycle measurements revealed that this compound induced apoptosis and reduced cells in the G1 phase accompanied by an increase of cells in the G2/M phase. Moreover, it showed hardly any effects on the cell membrane integrity. However, it also exhibited cytotoxicity against non-tumorigenic cells. Nevertheless, in summary, we could show that shikonin derivatives might be promising drug leads in the treatment of melanoma.

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Comparative Gene Expression Analysis in WM164 Melanoma Cells Revealed That β-β-Dimethylacrylshikonin Leads to ROS Generation, Loss of Mitochondrial Membrane Potential, and Autophagy Induction

Cited by 18 publications

References 48 publications

Investigating the Effects of Shikonin, Deoxyshikonin, and (β,β-Dimethylacryl)Shikonin on Melanoma Cell Lines

Investigating the Effects of Shikonin, Deoxyshikonin, and (β,β-Dimethylacryl)Shikonin on Melanoma Cell Lines

Oxidative Stress and Autophagy as Key Targets in Melanoma Cell Fate

Synthesis and Pharmacological In Vitro Investigations of Novel Shikonin Derivatives with a Special Focus on Cyclopropane Bearing Derivatives

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