Different Cell Responses to Hinokitiol Treatment Result in Senescence or Apoptosis in Human Osteosarcoma Cell Lines

Yang, Shun-Cheng; Chen, Hsuan-Ying; Chuang, Wan-Ling; Wang, Hui‐Chun; Hsieh, Cheng-Pu; Huang, Yi-Fu

doi:10.3390/ijms23031632

Cited by 6 publications

(8 citation statements)

References 33 publications

(48 reference statements)

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“…To the best of our knowledge, only one other tropolone has been evaluated in OS cells. Hinokitiol, also known as β‐Thujaplicin, induced cytotoxic effects in U‐2 OS and MG‐63 cells in MTT assays (Yang et al, 2022). Hinokitiol promoted cell cycle arrest at the S phase and a DNA damage response in both OS cell lines.…”

Section: Discussionmentioning

confidence: 99%

Investigation of the activity of a novel tropolone in osteosarcoma

Haney,

Feng,

Kollala

et al. 2023

Drug Development Research

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Osteosarcoma (OS) is a primary malignant bone tumor characterized by frequent metastasis, rapid disease progression, and a high rate of mortality. Treatment options for OS have remained largely unchanged for decades, consisting primarily of cytotoxic chemotherapy and surgery, thus necessitating the urgent need for novel therapies. Tropolones are naturally occurring seven‐membered non‐benzenoid aromatic compounds that possess antiproliferative effects in a wide array of cancer cell types. MO‐OH‐Nap is an α‐substituted tropolone that has activity as an iron chelator. Here, we demonstrate that MO‐OH‐Nap activates all three arms of the unfolded protein response (UPR) pathway and induces apoptosis in a panel of human OS cell lines. Co‐incubation with ferric chloride or ammonium ferrous sulfate completely prevents the induction of apoptotic and UPR markers in MO‐OH‐Nap‐treated OS cells. MO‐OH‐Nap upregulates transferrin receptor 1 (TFR1) protein levels, as well as TFR1, divalent metal transporter 1 (DMT1), iron‐regulatory proteins (IRP1, IRP2), ferroportin (FPN), and zinc transporter 14 (ZIP14) transcript levels, demonstrating the impact of MO‐OH‐Nap on iron‐homeostasis pathways in OS cells. Furthermore, MO‐OH‐Nap treatment restricts the migration and invasion of OS cells in vitro. Lastly, metabolomic profiling of MO‐OH‐Nap‐treated OS cells revealed distinct changes in purine and pyrimidine metabolism. Collectively, we demonstrate that MO‐OH‐Nap‐induced cytotoxic effects in OS cells are dependent on the tropolone's ability to alter cellular iron availability and that this agent exploits key metabolic pathways. These studies support further evaluation of MO‐OH‐Nap as a novel treatment for OS.

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Section: Discussionmentioning

confidence: 99%

Investigation of the activity of a novel tropolone in osteosarcoma

Haney,

Feng,

Kollala

et al. 2023

Drug Development Research

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“…Hinokitiol ( 12 , Figure 4 ) is a tropolone related, cyclic monoterpenoid that has been reported to show activity in anti-inflammatory and antioxidation processes while simultaneously promoting apoptosis and autophagy in cancer cells [ 62 , 63 ]. Western blot analysis of B16F10 murine melanoma cell line and 4T1 murine mammary carcinoma cell line showed this natural products potential of decreasing expression of heparanase, an enzyme known for its pro-metastasis effects in concentrations of 1 to 1250 nM.…”

Section: Biological Activities Of Monoterpenesmentioning

confidence: 99%

“…Cell viability assays of U2OS and MG-63 human osteosarcoma cell lines showed a concentration dependent decrease in cell viability with hinokitiol treatments the 10–80 μM concentration range [ 63 ]. Furthermore, this research conducted western blot analysis of MG-63 cells showing that with treatment of hinokitiol results in PARP and caspase-3 cleavage both of which being known mediators of apoptosis.…”

Section: Biological Activities Of Monoterpenesmentioning

confidence: 99%

“…Furthermore, this research conducted western blot analysis of MG-63 cells showing that with treatment of hinokitiol results in PARP and caspase-3 cleavage both of which being known mediators of apoptosis. Cleavage of PARP was noted after treatment of hinokitiol in concentrations as low as 20 μM and demonstrated a concentration dependent increase through 80 μM [ 63 ] suggesting this compound induces programed cell death. Unfortunately, the study did not analyze any of the aforementioned phenomena on healthy cell lines.…”

Section: Biological Activities Of Monoterpenesmentioning

confidence: 99%

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Recent Advances in Chemistry and Antioxidant/Anticancer Biology of Monoterpene and Meroterpenoid Natural Product

Barras,

Ling,

Rivas

2024

Molecules

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Monoterpenes and meroterpenes are two large classes of isoprene-based molecules produced by terrestrial plants and unicellular organisms as diverse secondary metabolites. The global rising incidence of cancer has led to a renewed interest in natural products. These monoterpenes and meroterpenes represent a novel source of molecular scaffolds that can serve as medicinal chemistry platforms for the development of potential preclinical leads. Furthermore, some of these natural products are either abundant, or their synthetic strategies are scalable as it will be indicated here, facilitating their derivatization to expand their scope in drug discovery. This review is a collection of representative updates (from 2016–2023) in biologically active monoterpene and meroterpenoid natural products and focuses on the recent findings of the pharmacological potential of these bioactive compounds as well as the newly developed synthetic strategies employed to access them. Particular emphasis will be placed on the anticancer and antioxidant potential of these compounds in order to raise knowledge for further investigations into the development of potential anti-cancer therapeutics. The mounting experimental evidence from various research groups across the globe regarding the use of these natural products at pre-clinical levels, renders them a fast-track research area worth of attention.

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“…However, in MG-63 cells with mutated p53, hinokitiol exposure significantly promotes cell apoptosis, not senescence. Suppression of autophagy by chloroquine enhances cellular senescence in U-2 OS cells and increases apoptosis in MG-63 cells [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

Attenuation of Endoplasmic Reticulum Stress Enhances Carvacrol-Induced Apoptosis in Osteosarcoma Cell Lines

Chiu

Chen

et al. 2023

Life

Self Cite

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Carvacrol is a monoterpenoid phenol that has excellent antimicrobial, antiviral, and anti-inflammatory activities. It can also improve wound healing. However, few studies have explored its antitumor effect on osteosarcoma. In this report, we tried to determine the potential efficacy of carvacrol against osteosarcoma cell lines. Our data revealed that carvacrol exposure inhibited the proliferation of osteosarcoma HOS and U-2 OS cells. In addition, carvacrol exposure enhanced the levels of cleaved PARP and caspase 3 and increased annexin V-positive cells, indicating that carvacrol exposure triggers apoptosis in osteosarcoma cell lines. Furthermore, the levels of reactive oxygen species (ROS) were enhanced after carvacrol exposure and cotreatment with NAC, the ROS scavenger, decreased the levels of cleaved PARP and caspase 3, suggesting the involvement of ROS in carvacrol-induced apoptosis. Importantly, we found that carvacrol exposure triggered several protein expressions related to endoplasmic reticulum (ER) stress, including GRP78/Bip, IRE1a, PERK, and CHOP, in HOS and U-2 OS cells, indicating that carvacrol exposure could result in ER stress in these cell lines. Cotreatment with the ER stress inhibitor 4-PBA increased the levels of cleaved PARP and caspase 3 and further suppressed cellular proliferation in carvacrol-exposed osteosarcoma cell lines. Overall, the results indicate that induced ER stress can protect cells from apoptosis, but increased ROS contributes to apoptosis in carvacrol-treated cells. In this report, we first demonstrate the role of ER stress in carvacrol-induced apoptosis and suggest that ER stress could be targeted to enhance the antitumor activity of carvacrol in osteosarcoma cell lines.

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Different Cell Responses to Hinokitiol Treatment Result in Senescence or Apoptosis in Human Osteosarcoma Cell Lines

Cited by 6 publications

References 33 publications

Investigation of the activity of a novel tropolone in osteosarcoma

Investigation of the activity of a novel tropolone in osteosarcoma

Recent Advances in Chemistry and Antioxidant/Anticancer Biology of Monoterpene and Meroterpenoid Natural Product

Attenuation of Endoplasmic Reticulum Stress Enhances Carvacrol-Induced Apoptosis in Osteosarcoma Cell Lines

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