Abstract
Background
Hepatocellular carcinoma (HCC) is the most prevalent type of liver cancer and the main cause of cancer death globally. The use of medicinal herbs as chemotherapeutic agents in cancer treatment is receiving attention as they possess no or minimum side effects. Isorhamnetin (IRN), a flavonoid, has been under attention for its anti-inflammatory and anti-proliferative properties in a number of cancers, including colorectal, skin, and lung cancers. However, the in vivo mechanism of isorhamnetin to suppress liver cancer has yet to be explored.
Methods and Result
HCC was induced by N-diethylnitrosamine (DEN) and carbon tetrachloride (CCL4) in Swiss albino mice. Isorhamnetin (100 mg/kg body weight) was given to examine its anti-tumor properties in HCC mice model. Histological analysis and liver function assays were performed to assess changes in liver anatomy. Probable molecular pathways were explored using immunoblot, qPCR, ELISA, and immunohistochemistry techniques. Isorhamnetin inhibited various pro-inflammatory cytokines to suppress cancer-inducing inflammation. Additionally, it regulated Akt and MAPKs to suppress Nrf2 signaling. Isorhamnetin activated PPAR-γ and autophagy while suppressing cell cycle progression in DEN + CCl4-administered mice. Additionally, isorhamnetin regulated various signaling pathways to suppress cell proliferation, metabolism, and epithelial–mesenchymal transition in HCC.
Conclusion
Regulating diverse cellular signaling pathways makes isorhamnetin a better anti-cancer chemotherapeutic candidate in HCC. Importantly, the anti-TNF-α properties of isorhamnetin could prove it a valuable therapeutic agent in sorafenib-resistant HCC patients. Additionally, anti-TGF-β properties of isorhamnetin could be utilized to reduce the EMT-inducing side effects of doxorubicin.
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Data availability
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Abbreviations
- ALT:
-
Alanine aminotransferase
- AST:
-
Aspartate aminotransferase
- ATG7:
-
Autophagy-related 7
- Bad:
-
BCL2-associated agonist of cell death
- CCl4 :
-
Carbon tetrachloride
- C/EBP-δ:
-
CCAAT/enhancer-binding protein delta
- DEN:
-
N-Diethylnitrosamine
- Doxo:
-
Doxorubicin
- ERK:
-
Extracellular signal-regulated kinase
- EMT:
-
Epithelial–mesenchymal transition
- GSK-3β:
-
Glycogen synthase kinase-3 beta:
- HCC:
-
Hepatocellular carcinoma
- HO-1:
-
Heme Oxygenase-1
- HRP:
-
Horseradish peroxidise
- IRN:
-
Isorhamnetin
- JNK:
-
C-Jun N-terminal kinase
- Keap1:
-
Kelch-like ECH-associated protein 1
- Lamp2A:
-
Lysosomal associated membrane protein-2
- MMP-9:
-
Matrix metalloproteinases 9
- Mcl-1:
-
Myeloid cell leukemia-1
- mTOR:
-
Mammalian target of rapamycin
- Nrf2:
-
Nuclear factor erythroid 2-related factor 2
- NSCLC:
-
Non-small cell lung carcinoma
- PPAR-γ:
-
Peroxisome proliferator-activated receptor-gamma
- ROS:
-
Reactive oxygen species
- RSK:
-
Ribosomal S6 kinase
- RUNX2:
-
Runt-related transcription factor 2
- SOD:
-
Superoxide dismutase
- SDS:
-
Sodium dodecyl sulfate
- SVR:
-
Sustained virological response
- STAT3:
-
Signal transducer and activator of transcription 3
- TGF-β:
-
Transforming growth factor beta
- TNF-α:
-
Tumor necrosis factor alpha
- YAP1:
-
Yes-associated protein 1
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The authors are deeply grateful to Ms. Noyel Ghosh and Ms. Ankita Mandal for their valuable inputs during the preparation of the manuscript.
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SS contributed to conceptualization, methodology, software, validation, data curation, formal analysis, investigation, writing of the original draft, visualization, and writing, reviewing, & editing of the manuscript. AKD contributed to methodology, validation, and writing, reviewing, & editing of the manuscript. SB contributed to conceptualization. RG contributed to conceptualization, validation, data curation, formal analysis, visualization, and writing, reviewing, & editing of the manuscript. PCS contributed to conceptualization, validation, data curation, formal analysis, visualization, and writing, reviewing, & editing of the manuscript. All authors read and approved the final manuscript.
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All the animal experiments were prosecuted according to the institutional ethical committee and with the permission of IAEC, CPCSEA (Committee for the Purpose of Control & Supervision on Experiments on Animals) and the Ministry of Environment and Forests, New Delhi, India [1796/GO/EReBiBt/S/14/CPCSEA].
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Sarkar, S., Das, A.K., Bhattacharya, S. et al. Isorhamnetin exerts anti-tumor activity in DEN + CCl4-induced HCC mice. Med Oncol 40, 188 (2023). https://doi.org/10.1007/s12032-023-02050-5
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DOI: https://doi.org/10.1007/s12032-023-02050-5