Identification of Small-Molecule Inhibitors for Osteosarcoma Targeted Therapy: Synchronizing In Silico, In Vitro, and In Vivo Analyses

Liu, Juan; Qi, Yue; Yu, Peng; Dong, Zhihong; Tang, Lu; Su, Xiaoyu; Liu, Lishuang; Chen, Cheng; Ramalingam, Murugan; Cheng, Lijia

doi:10.3389/fbioe.2022.921107

Cited by 3 publications

(1 citation statement)

References 36 publications

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“…Targeted therapies for OS have garnered interest, with small-molecule targeted inhibitors emerging as one of the most promising avenues ( 7 ). mTOR, a serine/threonine protein kinase, serves a pivotal role in regulating cell proliferation, differentiation, senescence and metabolism ( 8 - 10 ).…”

Section: Introductionmentioning

confidence: 99%

Therapeutic impacts of GNE‑477‑loaded H₂O₂ stimulus‑responsive dodecanoic acid‑phenylborate ester‑dextran polymeric micelles on osteosarcoma

Pan,

Zou,

Zhou

et al. 2024

Int J Mol Med

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Osteosarcoma (OS) is a highly malignant primary bone neoplasm that is the leading cause of cancer-associated death in young people. GNE-477 belongs to the second generation of mTOR inhibitors and possesses promising potential in the treatment of OS but dose tolerance and drug toxicity limit its development and utilization. The present study aimed to prepare a novel H 2 O 2 stimulus-responsive dodecanoic acid (DA)-phenylborate ester-dextran (DA-B-DEX) polymeric micelle delivery system for GNE-477 and evaluate its efficacy. The polymer micelles were characterized by morphology, size and critical micelle concentration. The GNE-477 loaded DA-B-DEX (GNE-477@DBD) tumor-targeting drug delivery system was established and the release of GNE-477 was measured. The cellular uptake of GNE-477@DBD by three OS cell lines (MG-63, U2OS and 143B cells) was analyzed utilizing a fluorescent tracer technique. The hydroxylated DA-B was successfully grafted onto dextran at a grafting rate of 3%, suitable for forming amphiphilic micelles. Following exposure to H 2 O 2 , the DA-B-DEX micelles ruptured and released the drug rapidly, leading to increased uptake of GNE-477@DBD by cells with sustained release of GNE-477. The in vitro experiments, including MTT assay, flow cytometry, western blotting and RT-qPCR, demonstrated that GNE-477@DBD inhibited tumor cell viability, arrested cell cycle in G1 phase, induced apoptosis and blocked the PI3K/Akt/mTOR cascade response. In vivo , through the observation of mice tumor growth and the results of H&E staining, the GNE-477@DBD group exhibited more positive therapeutic outcomes than the free drug group with almost no adverse effects on other organs. In conclusion, H 2 O 2 -responsive DA-B-DEX presents a promising delivery system for hydrophobic anti-tumor drugs for OS therapy.

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Section: Introductionmentioning

confidence: 99%

Therapeutic impacts of GNE‑477‑loaded H₂O₂ stimulus‑responsive dodecanoic acid‑phenylborate ester‑dextran polymeric micelles on osteosarcoma

Pan,

Zou,

Zhou

et al. 2024

Int J Mol Med

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Aucubin Induces Apoptotic Cell Death Through Caspase-dependent Pathways in Human Osteosarcoma MG-63 Cells

Cui,

Chen

2024

Pharmacognosy Magazine

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Background Osteosarcomas (OSs) are predominantly generated by mesenchymal cells, which commonly develop in the distal and upper regions of the bones. OS has high mortality rates and treatment failures, mostly due to the presence of lung metastases. Purpose The present work aimed to scrutinize the anticancer potentials of aucubin against OS human osteosarcoma (MG-63) cells. Methods The proliferation of the control and aucubin-treated MG-63 cells was studied by an XTT assay. Various fluorescent staining assays were done to assess the endogenous reactive oxygen species (ROS) accumulation and apoptosis in the aucubin-treated MG-63 cells. The caspase-3, -8, and -9 activities were investigated using the assay kits. Results The XTT assay results confirmed that the aucubin treatment considerably reduced the MG-63 cells. The findings of the various fluorescent staining assays evidenced that the aucubin treatment remarkably promoted endogenous ROS accumulation and apoptosis in the OS cells. The caspase activities were also improved in the OS cells after the aucubin treatment. Conclusion The results of this work show that aucubin treatments inhibit cell proliferation and trigger apoptosis in MG-63 cells, suggesting its potential as a promising anticancer agent. These findings will facilitate the future development of aucubin as a talented anticancer agent to treat OS.

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Tellurium-Doped Bioactive Glass Induces Ferroptosis in Osteosarcoma Cells Regardless of FSP1

Pańczyszyn,

Lallukka,

Gagliardi

et al. 2024

Antioxidants

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Human osteosarcoma (OS) is a rare tumor predominantly affecting long bones and characterized by a poor prognosis. Currently, the first line of intervention consists of the surgical resection of primary tumors combined with radiotherapy and chemotherapy, with a profound impact on the patient’s life. Since the surgical removal of OS frequently results in a large resection of bones, the use of biomaterials to sustain the stability of the remaining tissue and to stimulate bone regeneration is challenging. Moreover, residual neoplastic cells might be responsible for tumor recurrence. Here, we explored the potential of tellurium-ion-doped bioactive glass as a novel therapeutic intervention to both eradicate residual malignant cells and promote bone regeneration. Bioactive glass (BAG) has been extensively studied and employed in the field of regenerative medicine due to its osseointegration properties and ability to improve bone tissue regeneration. We found that the incorporation of tellurium (Te) in BAG selectively kills OS cells through ferroptosis while preserving the viability of hBMSCs and stimulating their osteodifferentiation. However, the mechanism of Te toxicity is still unclear: (i) Te-BAG generates lipid-ROS through LOXs activity but not iron overload; (ii) Te-dependent ferroptosis is mediated by GPX4 down-regulation; and (iii) the anti-ferroptotic activity of FSP1 is abrogated, whose expression confers the resistance of OS to the canonical induction of ferroptosis. Overall, our data show that Te-doped bioglass could represent an interesting biomaterial with both pro-ferroptotic activity towards residual cancer cells and pro-osteoregenerative activity.

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Identification of Small-Molecule Inhibitors for Osteosarcoma Targeted Therapy: Synchronizing In Silico, In Vitro, and In Vivo Analyses

Cited by 3 publications

References 36 publications

Therapeutic impacts of GNE‑477‑loaded H₂O₂ stimulus‑responsive dodecanoic acid‑phenylborate ester‑dextran polymeric micelles on osteosarcoma

Therapeutic impacts of GNE‑477‑loaded H₂O₂ stimulus‑responsive dodecanoic acid‑phenylborate ester‑dextran polymeric micelles on osteosarcoma

Aucubin Induces Apoptotic Cell Death Through Caspase-dependent Pathways in Human Osteosarcoma MG-63 Cells

Tellurium-Doped Bioactive Glass Induces Ferroptosis in Osteosarcoma Cells Regardless of FSP1

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Identification of Small-Molecule Inhibitors for Osteosarcoma Targeted Therapy: Synchronizing In Silico, In Vitro, and In Vivo Analyses

Cited by 3 publications

References 36 publications

Therapeutic impacts of GNE‑477‑loaded H2O2 stimulus‑responsive dodecanoic acid‑phenylborate ester‑dextran polymeric micelles on osteosarcoma

Therapeutic impacts of GNE‑477‑loaded H2O2 stimulus‑responsive dodecanoic acid‑phenylborate ester‑dextran polymeric micelles on osteosarcoma

Aucubin Induces Apoptotic Cell Death Through Caspase-dependent Pathways in Human Osteosarcoma MG-63 Cells

Tellurium-Doped Bioactive Glass Induces Ferroptosis in Osteosarcoma Cells Regardless of FSP1

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Product

Resources

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Therapeutic impacts of GNE‑477‑loaded H₂O₂ stimulus‑responsive dodecanoic acid‑phenylborate ester‑dextran polymeric micelles on osteosarcoma

Therapeutic impacts of GNE‑477‑loaded H₂O₂ stimulus‑responsive dodecanoic acid‑phenylborate ester‑dextran polymeric micelles on osteosarcoma