The combination of berberine and irradiation enhances anti-cancer effects via activation of p38 MAPK pathway and ROS generation in human hepatoma cells

AbstractThe objective of the present study was to extract ursolic acid (UA) from Ocimum sanctum, to synthesize its bioactive derivatives, evaluate the anti-cancer effect of its derivatives and to establish the possible mechanism of action. In the present report, we extracted UA from whole plant of O. sanctum, synthesized its novel derivatives and investigated their effect on homocysteine metabolism and dihydrofolate reductase (DHFR) activity of HepG2 cells. UA and its derivatives UA-1, UA-2 and UA-3 down-regulated DHFR activity and increased extracellular homocysteine. UA-2 showed significant anti-proliferation activity in cancer cells. Cancer cells have increased the requirement of pyrimidine base thymidylate due to rapid cell division. Thymidylate biosynthesis depends on sufficient pools of folate dependent enzymes like DHFR. In the present study, we examined the UA and its derivatives mediated perturbation of DHFR activity and extracellular homocysteine in HepG2 human hepatoma cells. After incubation with UA-2, a potent inhibition of DHFR activity was observed. Our results showed that derivatization of UA might adversely affect DHFR activity. Measurement of extracellular homocysteine indicated impaired one-carbon metabolism in cells treated with UA derivatives. In conclusion, our data suggest an anti-cancer role of UA and its derivatives via inhibition of one-carbon metabolism.

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p38 MAPK and NF-κB pathways are involved in naphtho[1,2-b] furan-4,5-dione induced anti-proliferation and apoptosis of human hepatoma cells

Cancer Letters ◽

10.1016/j.canlet.2010.02.017 ◽

2010 ◽

Vol 295 (1) ◽

pp. 92-99 ◽

Cited By ~ 45

Author(s):

Chien-Chih Chiu ◽

Jeff Yi-Fu Chen ◽

Kuwi-Li Lin ◽

Chi-Jung Huang ◽

Jin-Ching Lee ◽

...

Keyword(s):

P38 Mapk ◽

Hepatoma Cells ◽

Human Hepatoma ◽

Human Hepatoma Cells ◽

Proliferation And Apoptosis

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Involvement of p38 MAPK pathway in benzo(a)pyrene-induced human hepatoma cell migration and invasion

Environmental Science and Pollution Research ◽

10.1007/s11356-019-06733-3 ◽

2019 ◽

Vol 26 (35) ◽

pp. 35838-35845 ◽

Cited By ~ 1

Author(s):

Yadong Wang ◽

Li Shi ◽

Jiangmin Li ◽

Li Li ◽

Haiyu Wang ◽

...

Keyword(s):

Cell Migration ◽

P38 Mapk ◽

Mapk Pathway ◽

Hepatoma Cell ◽

Migration And Invasion ◽

Human Hepatoma ◽

Human Hepatoma Cell ◽

Cell Migration And Invasion ◽

P38 Mapk Pathway

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A Ruthenium(II) N-Heterocyclic Carbene (NHC) Complex with Naphthalimide Ligand Triggers Apoptosis in Colorectal Cancer Cells via Activating the ROS-p38 MAPK Pathway

International Journal of Molecular Sciences ◽

10.3390/ijms19123964 ◽

2018 ◽

Vol 19 (12) ◽

pp. 3964 ◽

Cited By ~ 10

Author(s):

Yasamin Dabiri ◽

Alice Schmid ◽

Jannick Theobald ◽

Biljana Blagojevic ◽

Wojciech Streciwilk ◽

...

Keyword(s):

Cancer Cells ◽

P38 Mapk ◽

Molecular Mechanisms ◽

Mapk Pathway ◽

P38 Mapk Pathway ◽

Anti Cancer ◽

Colorectal Cancer Cells ◽

Cellular Reactive Oxygen Species ◽

Cancer Types ◽

Apoptotic Effects

The p38 MAPK pathway is known to influence the anti-tumor effects of several chemotherapeutics, including that of organometallic drugs. Previous studies have demonstrated the important role of p38 both as a regulator and a sensor of cellular reactive oxygen species (ROS) levels. Investigating the anti-cancer properties of novel 1,8-naphthalimide derivatives containing Rh(I) and Ru(II) N-heterocyclic carbene (NHC) ligands, we observed a profound induction of ROS by the complexes, which is most likely generated from mitochondria (mtROS). Further analyses revealed a rapid and consistent activation of p38 signaling by the naphthalimide-NHC conjugates, with the Ru(II) analogue—termed MC6—showing the strongest effect. In view of this, genetic as well as pharmacological inhibition of p38α, attenuated the anti-proliferative and pro-apoptotic effects of MC6 in HCT116 colon cancer cells, highlighting the involvement of this signaling molecule in the compound’s toxicity. Furthermore, the influence of MC6 on p38 signaling appeared to be dependent on ROS levels as treatment with general- and mitochondria-targeted anti-oxidants abrogated p38 activation in response to MC6 as well as the molecule’s cytotoxic- and apoptogenic response in HCT116 cells. Altogether, our results provide new insight into the molecular mechanisms of naphthalimide-metal NHC analogues via the ROS-induced activation of p38 MAPK, which may have therapeutic interest for the treatment of various cancer types.

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