Investigation of ovatodiolide, a macrocyclic diterpenoid, as a potential inhibitor of oral cancer stem-like cells properties via the inhibition of the JAK2/STAT3/JARID1B signal circuit

Lin, Chun–Shu; Bamodu, Oluwaseun Adebayo; Kuo, Kuang Tai; Huang, Chih Ming; Liu, Shao‐Cheng; Wang, Chun Hua; Tzeng, Yew Min; Chao, Tsu Yi; Yeh, Chi Tai

doi:10.1016/j.phymed.2018.04.016

Cited by 22 publications

(14 citation statements)

References 20 publications

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“…Based on previous studies by our team, OV exhibits antibacterial, anti-inflammatory, and anticancer properties [8,9,22]. The present study provides an additional mechanistic insight into the ability of OV to suppress OSCC tumorigenesis by reducing the cargo of CSC-derived EVs.…”

Section: Discussionmentioning

confidence: 57%

“…In addition to the demonstrated ability of OV to inhibit carcinogenesis in different cancer types by our group [8][9][10]22], the present study demonstrated that treatment with OV significantly suppressed the ability of CAL27 (2.91-fold, p < 0.001) and SCC-15 (2.67-fold, p < 0.001) cells to form tumorspheres ( Figure 4A) with concomitant downregulation of PI3K, STAT3, TGFβ1, and β-catenin protein expression levels in OV-treated tumorspheres, compared to their control counterparts ( Figure 4B). Next, our comparative analysis of gene expression profiles of CSC_EVs from control and OV-treated groups showed that CSC_EVs from OV-treated cells contained significantly lower amounts of cargo loads of PI3K, TGF-β1, STAT3, AKT, and miR-21-5p, compared to control CSC_EVs ( Figure 4C).…”

Section: Ov Suppresses Oscc Oncogenicity By Reducing Exosomal Cargosmentioning

confidence: 99%

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Ovatodiolide Suppresses Oral Cancer Malignancy by Down-Regulating Exosomal Mir-21/STAT3/β-Catenin Cargo and Preventing Oncogenic Transformation of Normal Gingival Fibroblasts

Chen

Bamodu

et al. 2019

Cancers

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Oral squamous cell carcinoma (OSCC) is among the most commonly diagnosed malignancies in the world. Patients with OSCC often develop treatment resistance, resulting in a poor prognosis. Mounting evidence indicates that interactions between cancerous cells and other components of the tumor microenvironment (TME) determine their response to treatment. Herein, we examined the role of cancer stem cell-derived extracellular vesicles (CSC_EVs) generated from CAL27 and SCC-15 OSCC cells in the development of cisplatin (CDDP) resistance. We demonstrated that CSC_EVs enhance CDDP resistance, clonogenicity, and the tumorsphere formation potential of OSCC cells. Our bioinformatics analyses revealed that OSCC_EVs are enriched with microRNA (miR)-21-5p and are associated with increased metastasis, stemness, chemoresistance, and poor survival in patients with OSCC. Mechanistically, enhanced activity of CSC_EVs was positively correlated with upregulated Cancers 2020, 12, 56 2 of 16 β-catenin, phosphatidylinositol-3 kinase (PI3K), signal transducer and activator of transcription 3 (STAT3), mammalian target of rapamycin (mTOR), and transforming growth factor (TGF)-β1 messenger (m)RNA and protein expression levels. CSC_EVs also conferred a cancer-associated fibroblast (CAF) phenotype on normal gingival fibroblasts (NGFs), with the resultant CAFs enhancing the oncogenicity of OSCC cells. Interestingly, treatment with ovatodiolide (OV), the bioactive component of Anisomeles indica, suppressed OSCC tumorigenesis by reducing the cargo content of EVs derived from CSCs, suppressing self-renewal, and inhibiting the NGF-CAF transformation by disrupting EV-TME interactions. Moreover, by suppressing miR-21-5p, STAT3, and mTOR expressions in CSC_EVs, OV re-sensitized CSCs to CDDP and suppressed OSCC tumorigenesis. In vivo, treatment with OV alone or in combination with CDDP significantly reduced the tumor sphere-forming ability and decreased EV cargos containing mTOR, PI3K, STAT3, β-catenin, and miR-21-5p. In summary, our findings provide further strong evidence of OV's therapeutic effect in OSCC.

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Section: Discussionmentioning

confidence: 57%

Section: Ov Suppresses Oscc Oncogenicity By Reducing Exosomal Cargosmentioning

confidence: 99%

Ovatodiolide Suppresses Oral Cancer Malignancy by Down-Regulating Exosomal Mir-21/STAT3/β-Catenin Cargo and Preventing Oncogenic Transformation of Normal Gingival Fibroblasts

Chen

Bamodu

et al. 2019

Cancers

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“…Ganoderma lucidum extract (GLE) with anticancer activity inhibits the STAT3 signaling pathway thereby reducing the expression of phosphorylated and total STAT3 and OCT4 of breast CSCs (91). Ovatodiolide reduces the expression of genes, such as OCT4, and the formation of tumorspheres by inhibiting the JAK2/STAT3 signaling pathway, and cooperates with cisplatin to complete the treatment of oral cancer (104). Survivin is an apoptosis suppressor protein and is associated with chemoradiation resistance and metastasis of tumor cells (105).…”

Section: Signal Transducer and Activator Of Transcription Pathwaymentioning

confidence: 99%

The Role and Specific Mechanism of OCT4 in Cancer Stem Cells: A Review

Zhang

Han

Zhu

et al. 2020

IJSC

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Recently, evidences show that cancer stem cells (CSCs) are a type of cancer cell group with self-renewal and play a huge role in tumor recurrence, metastasis, and drug resistance. Finding new treatment directions and targets for cancer prognosis and reducing mortality has become a top priority. OCT4, as a transcription factor, participates in maintaining the stem characteristics of CSCs, but the mechanism of OCT4 is often overlooked. In this review, we try to illustrate the mechanism by which OCT4 plays a role in CSCs from the perspective of genetic modification of OCT4, non-coding RNA, complexes and signaling pathways associated with OCT4. Our ultimate goal is to provide new targets for cancer treatment to prolong the survival of cancer patients.

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“…Next, Ovatodiolide (Ova) is a macrocyclic diterpenoid, isolated from Anisomeles indica . It exhibited potent anticancer actions on glioblastoma, nasopharyngeal carcinoma, and oral cancer cells [ 23 , 24 , 26 ]. Mechanistically, Ova reduced the stemness markers (CD44, CD133, Sox2, Klf4, Nanog, and Oct4) of CSCs and decreased the expression of EMT genes [ 23 , 24 ].…”

Section: Phytomedicines Targeting Key Regulators Of Anti-cancer Drug Resistance In Cscsmentioning

confidence: 99%

“…It exhibited potent anticancer actions on glioblastoma, nasopharyngeal carcinoma, and oral cancer cells [ 23 , 24 , 26 ]. Mechanistically, Ova reduced the stemness markers (CD44, CD133, Sox2, Klf4, Nanog, and Oct4) of CSCs and decreased the expression of EMT genes [ 23 , 24 ]. It also modulated the JAK2/STAT3 signaling pathway by inhibiting either JAK2 or STAT3 protein, and thus dysregulated the gene transcription [ 24 ].…”

Section: Phytomedicines Targeting Key Regulators Of Anti-cancer Drug Resistance In Cscsmentioning

confidence: 99%

Phytomedicines Targeting Cancer Stem Cells: Therapeutic Opportunities and Prospects for Pharmaceutical Development

et al. 2021

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The presence of small subpopulations of cells within tumor cells are known as cancer stem cells (CSCs). These cells have been the reason for metastasis, resistance with chemotherapy or radiotherapy, and tumor relapse in several types of cancers. CSCs underwent to epithelial–mesenchymal transition (EMT) and resulted in the development of aggressive tumors. CSCs have potential to modulate numerous signaling pathways including Wnt, Hh, and Notch, therefore increasing the stem-like characteristics of cancer cells. The raised expression of drug efflux pump and suppression of apoptosis has shown increased resistance with anti-cancer drugs. Among many agents which were shown to modulate these, the plant-derived bioactive agents appear to modulate these key regulators and were shown to remove CSCs. This review aims to comprehensively scrutinize the preclinical and clinical studies demonstrating the effects of phytocompounds on CSCs isolated from various tumors. Based on the available convincing literature from preclinical studies, with some clinical data, it is apparent that selective targeting of CSCs with plants, plant preparations, and plant-derived bioactive compounds, termed phytochemicals, may be a promising strategy for the treatment of relapsed cancers.

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Investigation of ovatodiolide, a macrocyclic diterpenoid, as a potential inhibitor of oral cancer stem-like cells properties via the inhibition of the JAK2/STAT3/JARID1B signal circuit

Cited by 22 publications

References 20 publications

Ovatodiolide Suppresses Oral Cancer Malignancy by Down-Regulating Exosomal Mir-21/STAT3/β-Catenin Cargo and Preventing Oncogenic Transformation of Normal Gingival Fibroblasts

Ovatodiolide Suppresses Oral Cancer Malignancy by Down-Regulating Exosomal Mir-21/STAT3/β-Catenin Cargo and Preventing Oncogenic Transformation of Normal Gingival Fibroblasts

The Role and Specific Mechanism of OCT4 in Cancer Stem Cells: A Review

Phytomedicines Targeting Cancer Stem Cells: Therapeutic Opportunities and Prospects for Pharmaceutical Development

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