Sestrin2-Mediated Autophagy Contributes to Drug Resistance via Endoplasmic Reticulum Stress in Human Osteosarcoma

One contributor to the high mortality of osteosarcoma is its reduced sensitivity to chemotherapy, but the mechanism involved is unclear. Improving the sensitivity of osteosarcoma to chemotherapy is urgently needed to improve patient survival. We found that chemotherapy triggered apoptosis of human osteosarcoma cells in vitro and in vivo; this was accompanied by increased Sestrin2 expression. Importantly, autophagy was also enhanced with increased Sestrin2 expression. Based on this observation, we explored the potential role of Sestrin2 in autophagy of osteosarcoma. We found that Sestrin2 inhibited osteosarcoma cell apoptosis by promoting autophagy via inhibition of endoplasmic reticulum stress, and this process is closely related to the PERK-eIF2α-CHOP pathway. In addition, our study showed that low Sestrin2 expression can effectively reduce autophagy of human osteosarcoma cells after chemotherapy, increase p-mTOR expression, decrease Bcl-2 expression, promote osteosarcoma cell apoptosis, and slow down tumour progression in NU/NU mice. Sestrin2 activates autophagy by inhibiting mTOR via the PERK-eIF2α-CHOP pathway and inhibits apoptosis via Bcl-2. Therefore, our results explain one underlying mechanism of increasing the sensitivity of osteosarcoma to chemotherapy and suggest that Sestrin2 is a promising gene target.

Download Full-text

Artocarpin induces cell apoptosis in human osteosarcoma cells through endoplasmic reticulum stress and reactive oxygen species

Journal of Cellular Physiology ◽

10.1002/jcp.27986 ◽

2018 ◽

Vol 234 (8) ◽

pp. 13157-13168 ◽

Cited By ~ 3

Author(s):

Chiang‐Wen Lee ◽

Miao‐Ching Chi ◽

Tsung‐Ming Chang ◽

Ju‐Fang Liu

Keyword(s):

Reactive Oxygen Species ◽

Endoplasmic Reticulum ◽

Endoplasmic Reticulum Stress ◽

Cell Apoptosis ◽

Reactive Oxygen ◽

Oxygen Species ◽

Osteosarcoma Cells ◽

Human Osteosarcoma ◽

Human Osteosarcoma Cells

Download Full-text

Effects of Iron Chelation in Osteosarcoma

Current Cancer Drug Targets ◽

10.2174/1568009620666201230090531 ◽

2020 ◽

Vol 20 ◽

Author(s):

Maura Argenziano ◽

Alessandra Di Paola ◽

Chiara Tortora ◽

Daniela Di Pinto ◽

Elvira Pota ◽

...

Keyword(s):

Tumor Progression ◽

Cancer Progression ◽

Cell Cycle Progression ◽

Iron Chelation ◽

Iron Chelator ◽

Osteosarcoma Cell ◽

Osteosarcoma Cells ◽

Human Osteosarcoma ◽

Human Osteosarcoma Cells

Background: Osteosarcoma is an aggressive bone tumor. Itrepresents the principal cause of cancer-associated death in children.Considering the recent findings on the role of iron in cancer, iron chelation has been investigated for its antineoplastic properties in many tumors. Deferasirox is the most used iron chelator compound and in previous studies showed an anticancer effectinhematologic and solid malignancies. Eltrombopag is a Thrombopoietin receptor used in thrombocytopenia, that also binds and mobilize iron. It demonstrated an effect in iron overload conditions and also in contrasting cancer cells proliferation. Objective: We analyzed the effects of Deferasirox and Eltrombopag in Human Osteosarcoma cells, in the attempt to identify other therapeutic approaches for this tumor. Methods: We cultured and treated withDeferasirox and Eltrombopag, alone and in combination, two human osteosarcoma cell lines, MG63 and 143B. After 72h exposure, we performed RTqPCR, Western Blotting, Iron Assay and cytofluorimetric assays to evaluate the effect on viability, apoptosis, cell cycle progression and ROS production. Results: The iron chelating properties of the two compounds are confirmed also in Osteosarcoma, but we did not observe any direct effect on tumor progression. Discussion: We tested Deferasirox and Eltrombopag, alone and in combination, in Human Osteosarcoma cells for the first time and demonstrated that their iron chelating activity does not influence biochemical pathways related to cancer progression and maintenance. Conclusion: Although further investigations on possible effects mediated by cells of the tumor microenvironment could be of great interest, in vitro iron chelation in Osteosarcoma does not impair tumor progression.

Download Full-text

Bioinspired-Metalloporphyrin Magnetic Nanocomposite as a Reusable Catalyst for Synthesis of Diastereomeric (−)-Isopulegol Epoxide: Anticancer Activity Against Human Osteosarcoma Cells (MG-63)

Molecules ◽

10.3390/molecules24010052 ◽

2018 ◽

Vol 24 (1) ◽

pp. 52 ◽

Cited By ~ 4

Author(s):

Lucas Dias ◽

Ana Batista de Carvalho ◽

Sara Pinto ◽

Gilberto Aquino ◽

Mário Calvete ◽

...

Keyword(s):

Reusable Catalyst ◽

Osteosarcoma Cell ◽

Osteosarcoma Cells ◽

Human Osteosarcoma Cell Line ◽

Anticancer Effect ◽

Human Osteosarcoma ◽

Human Osteosarcoma Cells ◽

Human Osteosarcoma Cell ◽

Ic50 Values

In the present study, we developed a green epoxidation approach for the synthesis of the diastereomers of (−)-isopulegol benzyl ether epoxide using molecular oxygen as the oxidant and a hybrid manganese(III)-porphyrin magnetic reusable nanocomposite as the catalyst. High activity, selectivity, and stability were obtained, with up to four recycling cycles without the loss of activity and selectivity for epoxide. The anticancer effect of the newly synthesized isopulegol epoxide diastereomers was evaluated on a human osteosarcoma cell line (MG-63); both diastereomers showed similar in vitro potency. The measured IC50 values were significantly lower than those reported for other monoterpene analogues, rendering these epoxide isomers as promising anti-tumor agents against low prognosis osteosarcoma.

Download Full-text

Effects of Cabozantinib on Human G292 Osteosarcoma Cells

Medical Research Archives ◽

10.18103/mra.v9i9.2554 ◽

2021 ◽

Vol 9 (9) ◽

Author(s):

Longjie Chen ◽

Dinh Nguyen ◽

Ryan Kaminsky ◽

Jennifer Helfer ◽

Rosemary Dziak

Keyword(s):

Growth Factor ◽

Growth Factor Receptor ◽

Complex Nature ◽

Therapeutic Effects ◽

Osteosarcoma Cell ◽

Osteosarcoma Cells ◽

Human Osteosarcoma ◽

Human Osteosarcoma Cells ◽

Igf I

Cabozantinib (CBZ) N-(4-((6,7-dimethoxyquinolin-4-yl) oxy) phenyl)-N-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide) (XL184), an inhibitor of MET and vascular endothelial growth factor receptor (VEGFR-2), is an agent approved for the treatment of several types of carcinoma such as medullary thyroid and renal. Recent studies are encouraging for the effectiveness of CBZ in the treatment of osteosarcoma. Because of the complex nature of the microenvironment of osteosarcoma cell sites, in order to better understand the direct effects of CBZ on osteosarcoma cells, in vitro studies were conducted with the human osteosarcoma cell line, G292. Experiments were focused on the effects of CBZ on cell metabolic activity, differentiation, and apoptosis as well as the modulation of responses to growth factors such as platelet-derived growth factor (PDGF) and insulin like growth factor (IGF-I). The results indicate that CBZ can increase the activity of caspase 3/7 as an indicator of apoptosis as well as decrease cellular activity, measured by MTT assay and differentiation assessed by alkaline phosphatase activity. The drug partially downregulated the effects of PDGF on MTT activity and had significant inhibitory effects on the G292 cells response to IGF-I and production of VEGF. This study presents original information on responses of G292 human osteosarcoma cells to the chemotherapy agent, CBZ, and provides in vitro data consistent with the potential therapeutic effects of this agent for osteosarcoma.

Download Full-text

Ginsenoside Rg5 Inhibits Human Osteosarcoma Cell Proliferation and Induces Cell Apoptosis through PI3K/Akt/mTORC1-Related LC3 Autophagy Pathway

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/5040326 ◽

2021 ◽

Vol 2021 ◽

pp. 1-12

Author(s):

Ming-Yang Liu ◽

Fei Liu ◽

Yan-Jiao Li ◽

Jia-Ning Yin ◽

Yan-Li Gao ◽

...

Keyword(s):

Cell Proliferation ◽

Cell Apoptosis ◽

Caspase 3 ◽

Osteosarcoma Cell ◽

Osteosarcoma Cells ◽

Human Osteosarcoma ◽

Human Osteosarcoma Cells ◽

Human Osteosarcoma Cell ◽

Ginsenoside Rg5 ◽

Autophagy Pathway

The function and mechanism underlying the suppression of human osteosarcoma cells by ginsenoside-Rg5 (Rg5) was investigated in the present study. MG-63, HOS, and U2OS cell proliferation was determined by MTT assay after Rg5 treatment for 24 h. Rg5 inhibited human osteosarcoma cell proliferation effectively in a dose-dependent manner. The range of effective inhibitory concentrations was 160-1280 nM. Annexin V-FITC and PI double-staining assay revealed that Rg5 induced human osteosarcoma cell apoptosis. Western blotting, qRT-PCR, and FACS experiments revealed that Rg5 inhibited human osteosarcoma cells via caspase-3 activity which was related to the LC3-mediated autophagy pathway. Rg5 decreased the phosphorylation of PI3K, Akt, and mTORC1 activation. In contrast, LC3-mediated autophagy and caspase-3 activity increased significantly. A PI3K/AKT stimulator, IGF-1, reversed Rg5-induced cell autophagy and apoptosis in MG-63 cells. Collectively, the current study demonstrated that Rg5 induced human osteosarcoma cell apoptosis through the LC3-mediated autophagy pathway. Under physiological conditions, activation of PI3K/AKT/mTORC1 inhibits LC3 activity and caspase-3-related cell apoptosis. However, Rg5 activated LC3 activity by inhibiting the activation of PI3K/AKT/mTORC1. The present study indicated that Rg5 could be a promising candidate as a chemotherapeutic agent against human osteosarcoma.

Download Full-text

Anti-Metastatic and Anti-Angiogenic Effects of Curcumin Analog DK1 on Human Osteosarcoma Cells In Vitro

Pharmaceuticals ◽

10.3390/ph14060532 ◽

2021 ◽

Vol 14 (6) ◽

pp. 532

Author(s):

Muhammad Nazirul Mubin Aziz ◽

Nurul Fattin Che Rahim ◽

Yazmin Hussin ◽

Swee Keong Yeap ◽

Mas Jaffri Masarudin ◽

...

Keyword(s):

Cell Lines ◽

Safety Profile ◽

Quantitative Polymerase Chain Reaction ◽

Tube Formation ◽

Osteosarcoma Cell ◽

Curcumin Analog ◽

Human Osteosarcoma ◽

Human Osteosarcoma Cells ◽

Human Osteosarcoma Cell

Osteosarcoma (OS) is a life-threatening malignant bone tumor associated with poor prognosis among children. The survival rate of the patient is still arguably low even with intensive treatment provided, plus with the inherent side effects from the chemotherapy, which gives more unfavorable outcomes. Hence, the search for potent anti-osteosarcoma agent with promising safety profile is still on going. Natural occurring substance like curcumin has gained a lot of attention due to its splendid safety profile as well as it pharmacological advantages such as anti-metastasis and anti-angiogenesis. However, natural curcumin was widely known for its poor cellular uptake, which undermines all potential that it possesses. This prompted the development of synthetically synthesized curcuminoid analog, known as (Z)-3-hydroxy-1-(2-hydroxyphenyl)-3-phenylprop-2- en-1-one (DK1). In this present study, in vitro scratch assay, transwell migration/invasion assay, HUVEC tube formation assay, and ex vivo rat aortic ring assays were performed in order to investigate the anti-metastatic and anti-angiogenic potential of DK1. For further comprehension of DK1 mechanism on human osteosarcoma cell lines, microarray gene expression analysis, quantitative polymerase chain reaction (qPCR), and proteome profiler were adopted, providing valuable forecast from the expression of important genes and proteins related to metastasis and angiogenesis. Based on the data gathered from the bioassays, DK1 was able to inhibit the metastasis and angiogenesis of human osteosarcoma cell lines by significantly reducing the cell motility, number of migrated and invaded cells as well as the tube formation and micro-vessels sprouting. Additionally, DK1 also has significantly regulated several cancer pathways involved in OS proliferation, metastasis, and angiogenesis such as PI3K/Akt and NF-κB in both U-2 OS and MG-63. Regulation of PI3K/Akt caused up-regulation of genes related to metastasis inhibition, namely, PTEN, FOXO, PLK3, and GADD45A. Meanwhile, NF-κB pathway was regulated by mitigating the expression of NF-κB activator such as IKBKB and IKBKE in MG-63, whilst up-regulating the expression of NF-κB inhibitors such as NFKBIA and NFKBIE in U-2 OS. Finally, DK1 also has successfully hindered the metastatic and angiogenic capability of OS cell lines by down-regulating the expression of pro-metastatic genes and proteins like MMP3, COL11A1, FGF1, Endoglin, uPA, and IGFBP2 in U-2 OS. Whilst for MG-63, the significantly down-regulated oncogenes were Serpin E1, AKT2, VEGF, uPA, PD-ECGF, and Endoglin. These results suggest that curcumin analog DK1 may serve as a potential new anti-osteosarcoma agent due to its anti-metastatic and anti-angiogenic attributes.

Download Full-text

Mitochondrial genotypes and radiation-induced micronucleus formation in human osteosarcoma cells in vitro

Oncology Reports ◽

10.3892/or.8.3.615 ◽

2001 ◽

Cited By ~ 1

Author(s):

Ken Yoshida ◽

Hideya Yamazaki ◽

Shuji Ozeki ◽

Takehiro Inoue ◽

Yasuo Yoshioka ◽

...

Keyword(s):

Osteosarcoma Cells ◽

Micronucleus Formation ◽

Human Osteosarcoma ◽

Human Osteosarcoma Cells ◽

Radiation Induced

Download Full-text

Antiproliferative Properties of Oleuropein in Human Osteosarcoma Cells

Natural Product Communications ◽

10.1177/1934578x1601100418 ◽

2016 ◽

Vol 11 (4) ◽

pp. 1934578X1601100 ◽

Cited By ~ 1

Author(s):

Jose M. Moran ◽

Olga Leal-Hernandez ◽

Maria L. Canal-Macías ◽

Raul Roncero-Martin ◽

Rafael Guerrero-Bonmatty ◽

...

Keyword(s):

Cell Lines ◽

Osteosarcoma Cell ◽

Dependent Manner ◽

Osteosarcoma Cells ◽

Probit Regression ◽

Cytotoxic Effects ◽

Human Osteosarcoma ◽

Human Osteosarcoma Cells ◽

Mg63 Cells ◽

Human Osteosarcoma Cell

In this study, we evaluated the antiproliferative activity on two human osteosarcoma cell lines (MG-63 and Saos2) of oleuropein, an olive oil compound traditionally found in the Mediterranean diet. Oleuropein exhibited obvious cytotoxic effects on human osteosarcoma cells in a concentration- and time-dependent manner. Statistical analysis of IC50 by the Probit regression method suggested that oleuropein had similar toxic effects on both cell lines tested (IC50 range from 247.4–475.0 μM for MG63 cells and from 798.7–359.9 μM for Saos2 cells).

Download Full-text