Shikonin inhibits invasiveness of osteosarcoma through MMP13 suppression

Deng, Biyong; Qiu, Bing

doi:10.1007/s13277-015-3662-1

Cited by 22 publications

(32 citation statements)

References 37 publications

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“…Induction of cell death pathway by shikonin could be blocked a specific necroptosis inhibitor NEC-1, but not by general caspase inhibitor Z-VAD-fmk could block shikonin-induced of cell death pathway, suggesting the necroptotic pathway rather than apoptotic pathway is a signaling of choice in these experimental conditions [268, 282-295]. The number of K7 osteosarcoma necrotic cells caused by shikonin was decreased after being pretreated with NEC-1, as indicated in [282, 284]. Treatment with shikonin led to an increased expression of RIPK-1 and RIPK-3, while CASP-3, -6 and PARP were not activated in K7 and U2OS cells [282, 284].…”

Section: Necroptosis Signaling Pathways Cancer and Natural Compoundsmentioning

confidence: 99%

“…The loss of plasma membrane integrity was one of the morphologic characteristics of necrotic cell death, as indicated in [282-295]. Shikonin exerts a dramatic anticancer effect on both primary and metastatic osteosarcoma by inducing RIPK-1 and 3- dependent necroptosis [282, 284]. Induction of cell death pathway by shikonin could be blocked a specific necroptosis inhibitor NEC-1, but not by general caspase inhibitor Z-VAD-fmk could block shikonin-induced of cell death pathway, suggesting the necroptotic pathway rather than apoptotic pathway is a signaling of choice in these experimental conditions [268, 282-295].…”

Section: Necroptosis Signaling Pathways Cancer and Natural Compoundsmentioning

confidence: 99%

“…The number of K7 osteosarcoma necrotic cells caused by shikonin was decreased after being pretreated with NEC-1, as indicated in [282, 284]. Treatment with shikonin led to an increased expression of RIPK-1 and RIPK-3, while CASP-3, -6 and PARP were not activated in K7 and U2OS cells [282, 284]. Size of primary osteosarcoma tumors and lung metastases were significantly reduced by shikonin treatment accompanied the elevated levels for RIPK-1 and RIPK-3 proteins [282, 284].…”

Section: Necroptosis Signaling Pathways Cancer and Natural Compoundsmentioning

confidence: 99%

“…Treatment with shikonin led to an increased expression of RIPK-1 and RIPK-3, while CASP-3, -6 and PARP were not activated in K7 and U2OS cells [282, 284]. Size of primary osteosarcoma tumors and lung metastases were significantly reduced by shikonin treatment accompanied the elevated levels for RIPK-1 and RIPK-3 proteins [282, 284]. Shikonin was observed to induce necroptotic cell death in cancer cells including drug- and apoptosis-resistant cancer cells that overexpress P-glycoprotein, multidrug resistance protein-1 (MRP1), breast cancer resistance protein-1 (BCRP1), BCL-2, or BCL-xL [282].…”

Section: Necroptosis Signaling Pathways Cancer and Natural Compoundsmentioning

confidence: 99%

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Natural Compounds As Modulators of Non-apoptotic Cell Death in Cancer Cells

Guamán-Ortiz

Orellana²,

Ratovitski³

2017

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Cell death is an innate capability of cells to be removed from microenvironment, if and when they are damaged by multiple stresses. Cell death is often regulated by multiple molecular pathways and mechanism, including apoptosis, autophagy, and necroptosis. The molecular network underlying these processes is often intertwined and one pathway can dynamically shift to another one acquiring certain protein components, in particular upon treatment with various drugs. The strategy to treat human cancer ultimately relies on the ability of anticancer therapeutics to induce tumor-specific cell death, while leaving normal adjacent cells undamaged. However, tumor cells often develop the resistance to the drug-induced cell death, thus representing a great challenge for the anticancer approaches. Numerous compounds originated from the natural sources and biopharmaceutical industries are applied today in clinics showing advantageous results. However, some exhibit serious toxic side effects. Thus, novel effective therapeutic approaches in treating cancers are continued to be developed. Natural compounds with anticancer activity have gained a great interest among researchers and clinicians alike since they have shown more favorable safety and efficacy then the synthetic marketed drugs. Numerous studies in vitro and in vivo have found that several natural compounds display promising anticancer potentials. This review underlines certain information regarding the role of natural compounds from plants, microorganisms and sea life forms, which are able to induce non-apoptotic cell death in tumor cells, namely autophagy and necroptosis.

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Section: Necroptosis Signaling Pathways Cancer and Natural Compoundsmentioning

confidence: 99%

Section: Necroptosis Signaling Pathways Cancer and Natural Compoundsmentioning

confidence: 99%

Section: Necroptosis Signaling Pathways Cancer and Natural Compoundsmentioning

confidence: 99%

Section: Necroptosis Signaling Pathways Cancer and Natural Compoundsmentioning

confidence: 99%

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Natural Compounds As Modulators of Non-apoptotic Cell Death in Cancer Cells

Guamán-Ortiz

Orellana²,

Ratovitski³

2017

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“…Recently, we reported that high-dose of Shikonin had prompt but profound anti-tumor effect on both primary and metastatic OS, through inducing RIP1 and RIP3-dependent cancer cell necroptosis [26]. Moreover, Shikonin inhibits OS cell invasion through suppression of MMP13 [27]. However, the underlying mechanisms remain unknown.…”

Section: Introductionmentioning

confidence: 99%

TIPE2 Mediates the Suppressive Effects of Shikonin on MMP13 in Osteosarcoma Cells

Deng¹,

Feng²,

Deng³

2015

Cell Physiol Biochem

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Background/Aims: Osteosarcoma (OS) is a primary malignant bone tumor in humans, and is notorious mainly for its distal metastases. We have recently shown that Shikonin, an effective constituent extracted from Chinese medicinal herb, inhibits OS cell invasion through suppression of matrix metalloproteinase 13 (MMP13). However, the underlying mechanisms remain unknown. Methods: Here, we studied the levels of tumor necrosis factor (TNF)-alpha-induced protein 8-like 2 (TIPE2) in OS cells upon Shikonin treatment. TIPE2 levels were adapted in OS cell lines through transfection with plasmids carrying transgene or short-hairpin interference RNA (shRNA), and the effects of TIPE2 adaptation on MMP13 and cell invasiveness were evaluated by RT-qPCR, Western blot, ELISA and transwell cell migration assay, respectively. TIPE2 levels in OS specimens from patients were examined and correlated with cancer metastases and patient survival. Results: We found that Shikonin dose-dependently decreased MMP13 levels, and increased TIPE2 levels in two OS cell lines, U2OS and SaOS-2. Overexpression of TIPE2 in U2OS significantly suppressed MMP13 levels and cell invasiveness. Depletion of TIPE2 in SaOS-2 cells significantly increased MMP13 levels and cell invasiveness. Moreover, TIPE2 levels in OS specimens were significantly decreased, compared to adjacent non-cancer bone tissue. Lower TIPE2 levels correlated with higher incidence of metastases and worse 5-year survival. Conclusion: TIPE2 mediates the suppressive effects of Shikonin on MMP13 in osteosarcoma cells, and TIPE2 may be a novel therapeutic target for OS.

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