Dual treatment with shikonin and temozolomide reduces glioblastoma tumor growth, migration and glial-to-mesenchymal transition

Matias, Diana; Balça-Silva, Joana; Dubois, Luiz Gustavo; Pontes, Bruno; Ferrer, Valéria Pereira; Rosário, Luciane; Carmo, Anália do; Echevarria-Lima, Juliana; Sarmento‐Ribeiro, Ana Bela; Lopes, María Celeste; Moura‐Neto, Vivaldo

doi:10.1007/s13402-017-0320-1

Cited by 43 publications

(20 citation statements)

References 47 publications

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“…Furthermore, the most important cell‐cell contact factor, E‐cadherin, is rarely expressed in gliomas (Iwadate, ). Gliomas adopt a phenotype that could be considered mesenchymal in several aspects, and therefore the term “glial‐to‐mesenchymal transition (GMT)” or EMT‐like process has been proposed (Mahabir et al, ; Matias et al, ). The differences between classical EMT and the glial‐mesenchymal changes have just started to be uncovered (Iser et al, ; Kahlert, Nikkhah, & Maciaczyk, ).…”

Section: Malignant Alterations Of Glioma Cells Increase Their Invasionmentioning

confidence: 99%

“…Interestingly, concomitant treatment of GBM‐derived cells with temozolomide and shikonin (SHK, a naphthoquinone with anti‐tumor properties), suppressed the EMT‐like process. This treatment reduced GBM cell proliferation and migration, which were followed by decreased expression of Slug, vimentin, MMP‐2, MMP‐9, and β3 integrin via the inactivation of PI3K/Akt signaling (Matias et al, ).…”

Section: Malignant Alterations Of Glioma Cells Increase Their Invasionmentioning

confidence: 99%

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Glioma infiltration and extracellular matrix: key players and modulators

Ferrer

Moura‐Neto

Mentlein

2018

Glia

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158

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An outstanding characteristic of gliomas is their infiltration into brain parenchyma, a property that impairs complete surgical resection; consequently, these tumors might recur, resulting in a high mortality rate. Gliomas invade along preferential routes, such as those along white matter tracts and in the perineuronal and perivascular spaces. Brain extracellular components and their partners and modulators play a crucial role in glioma cell invasion. This review presents an extensive survey of the literature, showing how the brain extracellular matrix (ECM) is modulated during the glioma infiltration process. We explore aspects of ECM interaction with glioma cells, reviewing the main glycosaminoglycans, glycoproteins and proteoglycans. We discuss the roles of ECM-binding proteins, including CD44, RHAMM, integrins and axonal guidance molecules, and highlight the role of proteases and glycosidases in glioma infiltration; in binding and release chemokines, cytokines and growth factors; and in generating new bioactive ECM fragments. We also consider the roles of cytoskeletal signaling, angiogenesis, miRNAs and the glial-to-mesenchymal transition linked to glioma invasion. We closely discuss therapeutic approaches based on the modulation of the extracellular matrix, targeting the control of glioma infiltration, its relative failure in clinical trials, and potential means to overcome this difficulty.

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Section: Malignant Alterations Of Glioma Cells Increase Their Invasionmentioning

confidence: 99%

Section: Malignant Alterations Of Glioma Cells Increase Their Invasionmentioning

confidence: 99%

Glioma infiltration and extracellular matrix: key players and modulators

Ferrer

Moura‐Neto

Mentlein

2018

Glia

Self Cite

158

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“…Then, the C max of shikonin in humans is calculated to be 37.4 μM. c AUC ratios were calculated using Equation 1 shown in Section 2. used in clinical trials (Matias et al, 2017;Zhang et al, 2013). Taken together, the combined application of shikonin with other hCE2…”

Section: Discussionmentioning

confidence: 98%

“…The results of this study indicate that shikonin shows significant inhibitory effects on the activity of hCE2 in three different substrates. In addition, shikonin is shown to be a potent inhibitor of topoisomerase I, which inhibits the proliferation and migration capacities of bladder cancer cells and glioblastoma, with low toxicity towards normal cells, and has been used in clinical trials (Matias et al, ; Zhang et al, ). Taken together, the combined application of shikonin with other hCE2 substrate drugs will open up new opportunities to develop combination therapeutic strategies.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, shikonin has been reported to have potent antitumor effects against various tumors, including osteosarcoma, leukemia, breast cancer, and carcinoma of salivary gland (Chang, Huang, Chiang, Yeh, & Hsu, 2010;Mao, Yu, Li, & Li, 2008;Yao & Zhou, 2010). Matias et al (2017) found that glioblastomas-derived cells treated with a combination of shikonin and temozolomide showed decreases in proliferation and migration capacities.…”

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confidence: 99%

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Evidence for Shikonin acting as an active inhibitor of human carboxylesterases 2: Implications for herb–drug combination

Cao

et al. 2018

Phytotherapy Research

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Shikonin, a natural naphthoquinone compound derived from the herb Lithospermum erythrorhizon, is widely used for its various pharmacological activities. However, its potential interactions with other medications by inhibiting human carboxylesterases 2 (hCE2) remain unknown. In this study, the inhibitory effects of shikonin on the activity of hCE2 in human liver microsomes are investigated by using fluorescein diacetate (FD), N-(2-butyl-1,3-dioxo-2,3-dihydro-1H-phenalen-6-yl)-2-chloroacetamide (NCEN), and CPT-11 as substrates of hCE2. The results demonstrate that shikonin significantly inhibits the activity of hCE2 when FD and NCEN are used as substrates, whereas the half inhibition concentration value of shikonin increased by 5-30 times when CPT-11 was used as the substrate. The inhibition types of shikonin against hCE2 activity reflected by 3 substrates were all best fit to noncompetitive manners. In addition, shikonin was found to distinctly suppress endogenous hCE2 activity, characterized with attenuated fluorescence. Furthermore, for drugs metabolized by hCE2 with the similar binding sites with FD or NCEN, the estimated magnitudes of area under the curve variation were approximately 9-357% in the presence of shikonin. Also, the area under the curve of CPT-11 could be increased by 1-14% following administration of shikonin. These findings have clear clinical implications for the combination of shikonin and hCE2-metabolizing prodrugs.

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The multifaceted therapeutical role of low‐density lipoprotein receptor family in high‐grade glioma

Mastrantuono,

Ghibaudi,

Matias

et al. 2024

Molecular Oncology

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The diverse roles of the low‐density lipoprotein receptor family (LDLR) have been associated with many processes critical to maintaining central nervous system (CNS) health and contributing to neurological diseases or cancer. In this review, we provide a comprehensive understanding of the LDLR's involvement in common brain tumors, specifically high‐grade gliomas, emphasizing the receptors' critical role in the pathophysiology and progression of these tumors due to LDLR's high expression. We delve into LDLR's role in regulating cellular uptake and transport through the brain barrier. Additionally, we highlight LDLR's role in activating several signaling pathways related to tumor proliferation, migration, and invasion, engaging readers with an in‐depth understanding of the molecular mechanisms at play. By synthesizing current research findings, this review underscores the significance of LDLR during tumorigenesis and explores its potential as a therapeutic target for high‐grade gliomas. The collective insights presented here contribute to a deeper appreciation of LDLR's multifaceted roles and implications for physiological and pathological states, opening new avenues for tumor treatment.

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Dual treatment with shikonin and temozolomide reduces glioblastoma tumor growth, migration and glial-to-mesenchymal transition

Abstract: From our results we conclude that dual treatment with SHK and TMZ may constitute a powerful new tool for GBM treatment by reducing therapy resistance and tumor recurrence.

Cited by 43 publications

References 47 publications

Glioma infiltration and extracellular matrix: key players and modulators

Glioma infiltration and extracellular matrix: key players and modulators

Evidence for Shikonin acting as an active inhibitor of human carboxylesterases 2: Implications for herb–drug combination

The multifaceted therapeutical role of low‐density lipoprotein receptor family in high‐grade glioma

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