Kaempferide exhibits an anticancer effect against hepatocellular carcinoma in vitro and in vivo.
Hepatocellular carcinoma
Kaempferide
N1S1 HCC model
Journal
Naunyn-Schmiedeberg's archives of pharmacology
ISSN: 1432-1912
Titre abrégé: Naunyn Schmiedebergs Arch Pharmacol
Pays: Germany
ID NLM: 0326264
Informations de publication
Date de publication:
10 2023
10 2023
Historique:
received:
08
11
2022
accepted:
17
03
2023
medline:
13
9
2023
pubmed:
30
3
2023
entrez:
29
3
2023
Statut:
ppublish
Résumé
Phytochemicals have been promising candidates for cancer therapy, affecting various cancer initiation and progression stages. Kaempferide is a mono methoxy flavone that shows potent anticancer effects on multiple cancers both in vitro and in vivo. We evaluated the anticancer activity of kaempferide against HCC using an MTT ((3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay. HepG2, Huh7, and N1S1 were used for preliminary in vitro studies. This is followed by an apoptosis analysis assessed by caspase-3 and 9. The in vivo effects of the compound were studied in the N1S1 orthotopically injected SD (Sprague Dawley) rat model, where the animal was given kaempferide (25 mg/kg thrice a week) and vehicle (Cremophor:ethanol) iv. The expression of caspase-9 and a critical tumor marker, transforming growth factor beta 1 (TGF-β 1), were assessed in both control and treatment tumor samples. Kaempferide-induced dose-dependent cytotoxicity in three HCC cell lines (HepG2: IC50 = 27.94 ± 2.199 µM; Huh7: IC50 = 25.65 ± 0.956 µM; and N1S1: IC50 = 15.18 ± 3.68 µM). Furthermore, caspase-dependent apoptosis was confirmed in vitro. Kaempferide showed a significant reduction in tumor size and tumor volume in vivo. Histopathological evaluation by hematoxylin and eosin (H&E) staining confirmed that altered cells were significantly demolished in the kaempferide-treated animals, which correlates with tumor reduction compared to the vehicle-treated group. Caspase-9 levels were also found to be increased in the treatment group. TGF-β 1, a crucial marker in invasion and metastasis of liver cancer, was also downregulated in the treatment group (control = 207.8 ± 22.9 pg/mL and kaempferide-treated = 157.3 ± 13.8 pg/mL). We report for the first time the potential of kaempferide as a promising alternative against HCC, which further warrants its clinical validation.
Identifiants
pubmed: 36988659
doi: 10.1007/s00210-023-02468-8
pii: 10.1007/s00210-023-02468-8
doi:
Substances chimiques
Caspase 9
EC 3.4.22.-
kaempferide
508XL61MPD
Transforming Growth Factor beta
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2461-2467Informations de copyright
© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
Références
Abotaleb M, Samuel SM, Varghese E, Varghese S, Kubatka P, Liskova A, et al (2019) Flavonoids in cancer and apoptosis. Cancers (Basel). 11(1). https://doi.org/10.3390/cancers11010028
Baby J, Devan AR, Kumar AR, Gorantla JN, Nair B, Aishwarya TS, Nath LR (2021) Cogent role of flavonoids as key orchestrators of chemoprevention of hepatocellular carcinoma: a review. J Food Biochem. 45(7):e13761. https://doi.org/10.1111/jfbc.13761
doi: 10.1111/jfbc.13761
pubmed: 34028054
Chan LL, Chan SL (2018) Treatment of high-burden hepatocellular carcinoma: an oncologist perspective. Hepatoma Res 4(2):5. https://doi.org/10.20517/2394-5079.2017.49
doi: 10.20517/2394-5079.2017.49
Chen H, Cai B, Kun L, Hua Q (2021a) miR ‑ 27a ‑ 3p regulates the inhibitory influence of endothelin 3 on the tumorigenesis of papillary thyroid cancer cells. 1–14. https://doi.org/10.3892/mmr.2021.11882
Chen Y, Hao E, Zhang F, Du Z, Xie J, Chen F, et al (2021b) Identifying Active Compounds and mechanism of camellia nitidissima chi on anti-colon cancer by network pharmacology and experimental validation. Evidence-based Complement Altern Med. 2021b. https://doi.org/10.1155/2021/7169211
Choudhari AS, Mandave PC, Deshpande M, Ranjekar P, Prakash O (2020) Phytochemicals in cancer treatment: from preclinical studies to clinical practice. Front Pharmacol. 10. https://doi.org/10.3389/fphar.2019.01614
Cui W, Gu F, Hu KQ (2009) Effects and mechanisms of silibinin on human hepatocellular carcinoma xenografts in nude mice. World J Gastroenterol 15(16):1943–1950. https://doi.org/10.3748/wjg.15.1943
doi: 10.3748/wjg.15.1943
pubmed: 19399925
pmcid: 2675083
Davis GL, Dempster J, Meler JD, Orr DW, Walberg MW, Brown B et al (2008) Hepatocellular carcinoma: management of an increasingly common problem. Baylor Univ Med Cent Proc 21(3):266–280. https://doi.org/10.1080/08998280.2008
doi: 10.1080/08998280.2008
Devan AR, Pavithran K, Nair B, Murali M, Nath LR (2022b) Deciphering the role of transforming growth factor-beta 1 as a diagnostic-prognostic-therapeutic candidate against hepatocellular Carcinoma. World J Gastroenterol 28(36):5250–5264. https://doi.org/10.3748/wjg.v28.i36.5250
doi: 10.3748/wjg.v28.i36.5250
pubmed: 36185626
pmcid: 9521521
Devan AR, Nair BL, Nath LR (2022a) Translational phytomedicines against cancer: promise and hurdles. Adv Pharm Bullet, 1. https://doi.org/10.34172/apb.2023.023
Elnaggar MH, Abushouk AI, Hassan AHE, Lamloum HM, Benmelouka A, Moatamed SA et al (2021) Nanomedicine as a putative approach for active targeting of hepatocellular Carcinoma. Semin Cancer Biol 69:91–99. https://doi.org/10.1016/j.semcancer.2019.08.016
doi: 10.1016/j.semcancer.2019.08.016
pubmed: 31421265
Gao L, Zhang W, Zhong WQ, Liu ZJ, Li HM, Yu ZL et al (2018) Tumor associated macrophages induce epithelial to mesenchymal transition via the EGFR/ERK1/2 pathway in head and neck squamous cell carcinoma. Oncol Rep 40(5):2558–2572. https://doi.org/10.3892/or.2018.6657
doi: 10.3892/or.2018.6657
pubmed: 30132555
pmcid: 6151899
Gopakumar L, Sreeranganathan M, Chappan S, James S, Gowd GS, Manohar M, Sukumaran A, Unni AKK, Nair SV, Koyakutty M (2022) Enhanced oral bioavailability and antitumor therapeutic efficacy of sorafenib administered in core–shell protein nanoparticle. Drug Deliv Transl Res 12(11):2824–2837. https://doi.org/10.1007/s13346-022-01142-5
doi: 10.1007/s13346-022-01142-5
pubmed: 35678961
Jiang Z, Wang J, Chen X, Wang X, Wang T, Zhu Z et al (2018) Simultaneous determination of kaempferide, kaempferol and isorhamnetin in rat plasma by ultra-high performance liquid chromatography-tandem mass spectrometry and its application to a pharmacokinetic study. J Braz Chem Soc. 29(3):535–42. https://doi.org/10.21577/0103-5053.20170166
doi: 10.21577/0103-5053.20170166
Kopustinskiene DM, Jakstas V, Savickas A, Bernatoniene J (2020) Flavonoids as anticancer agents. Nutrients. 12(2). https://doi.org/10.3390/nu12020457
Kudo M, Trevisani F, Abou-Alfa GK, Rimassa L (2017) Hepatocellular carcinoma: therapeutic guidelines and medical treatment. Liver Cancer. 6:16–26. https://doi.org/10.1159/000449343
doi: 10.1159/000449343
Kumar AR, Devan AR, Nair B, Nath LR (2021) Anti-VEGF mediated immunomodulatory role of phytochemicals: scientific exposition for plausible HCC treatment. Curr Drug Targets 22(11):1288–1316. https://doi.org/10.2174/1389450122666210203194036
doi: 10.2174/1389450122666210203194036
pubmed: 33538672
Li Y, Martin RCG (2011) Herbal medicine and hepatocellular carcinoma: applications and challenges. Evid Based Complement Alternat Med. https://doi.org/10.1093/ecam/neq044
Li KE, Yuan C (2020) MicroRNA ‑ 103 modulates tumor progression by targeting KLF7 in non ‑ small cell lung cancer. 1013–28. https://doi.org/10.3892/ijmm.2020.4649
Li H, Li SM, Luo YH, Xu WT, Zhang Y, Zhang T et al (2020) Kaempferide induces G0/G1 phase arrest and apoptosis via ROS-mediated signaling pathways in A549 human lung cancer cells. 15(7). https://doi.org/10.1177/1934578X20935226
McIlwain DR, Berger T, Mak TW (2013) Caspase functions in cell death and disease. Cold Spring Harb Perspect Biol 5(4):1–28. https://doi.org/10.1101/cshperspect.a008656
doi: 10.1101/cshperspect.a008656
Nair B, Nath LR (2020) Inevitable role of TGF-β1 in progression of nonalcoholic fatty liver disease. J Recept Signal Transduct 40(3):195–200. https://doi.org/10.1080/10799893.2020.1726952
doi: 10.1080/10799893.2020.1726952
Nair B, Anto RJ, Sabitha M, Nath LR (2020) Kaempferol-mediated sensitization enhances chemotherapeutic efficacy of sorafenib against hepatocellular carcinoma: an in silico and in vitro approach. Adv Pharm Bull. 10(3):472–6. https://doi.org/10.34172/apb.2020.058
doi: 10.34172/apb.2020.058
pubmed: 32665908
pmcid: 7335979
Nath LR, Gorantla JN, Joseph SM, Antony J, Thankachan S, Menon DB et al (2015) Kaempferide, the most active among the four flavonoids isolated and characterized from Chromolaena odorata, induces apoptosis in cervical cancer cells while being pharmacologically safe. RSC Adv 5(122):100912–100922. https://doi.org/10.1039/C5RA19199H
doi: 10.1039/C5RA19199H
Ranjan A, Ramachandran S, Gupta N, Kaushik I, Wright S, Srivastava S et al (2019) Role of phytochemicals in cancer prevention. Int J Mol Sci. 20(20). https://doi.org/10.3389/fphar.2019.01614
Sharma N, Biswas S, Al-Dayan N, Alhegaili AS, Sarwat M (2021) Antioxidant role of kaempferol in prevention of hepatocellular carcinoma. Antioxidant. 10(9). https://doi.org/10.3390/antiox10091419
Slika H, Mansour H, Wehbe N, Nasser SA, Iratni R, Nasrallah G et al (2022) Therapeutic potential of flavonoids in cancer: ROS-mediated mechanisms. Biomed Pharmacother. 146:112442. https://doi.org/10.1016/j.biopha.2021.112442
doi: 10.1016/j.biopha.2021.112442
pubmed: 35062053
Tang W, Chen Z, Zhang W, Cheng Y, Zhang B, Wu F et al (2020) The mechanisms of sorafenib resistance in hepatocellular Carcinoma: theoretical basis and therapeutic aspects. Signal Transduct Target Ther. 5(1). https://doi.org/10.1038/s41392-020-0187-x
Wang CH, Wey KC, Mo LR, Chang KK, Lin RC, Kuo JJ (2015) Current trends and recent advances in diagnosis, therapy, and prevention of hepatocellular carcinoma. Asian Pac J Cancer Prev. 16:3595–604. https://doi.org/10.7314/apjcp.2015.16.9.3595
doi: 10.7314/apjcp.2015.16.9.3595
pubmed: 25987009
Wang Z, Jiang C, Chen W, Zhang G, Luo D, Cao Y et al (2014) Baicalein induces apoptosis and autophagy via endoplasmic reticulum stress in hepatocellular carcinoma cells. Biomed Res Int. https://doi.org/10.1155/2014/732516
Yusuf H, Kamarlis RK, Yusni Y, Fahriani M (2021) The anticancer activity of ethanol extract of Chromolaena odorata leaves in 7,12-Dimethylbenz[a]anthracene in (DMBA) induced breast cancer Wistar rats (Rattus novergicus). Pharmacia 68(2):493–499. https://doi.org/10.3897/pharmacia.68.e63956
doi: 10.3897/pharmacia.68.e63956
Zhang HW, Hu JJ, Fu RQ, Liu X, Zhang YH, Li J et al (2018) Flavonoids inhibit cell proliferation and induce apoptosis and autophagy through downregulation of PI3Kγ mediated PI3K/AKT/mTOR/p70S6K/ULK signaling pathway in human breast cancer cells. Sci Reports 2018 81. 8(1):1–13. https://www.nature.com/articles/s41598-018-29308-7