ANTITUMOR EFFECTS OF CURCUMIN, ALONE OR IN COMBINATION WITH CISPLATIN OR DOXORUBICIN, ON HUMAN HEPATIC CANCER CELLS. ANALYSIS OF THEIR POSSIBLE RELATIONSHIP TO CHANGES IN NF-KB ACTIVATION LEVELS AND IAP GENE EXPRESSION

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Abstract

The hepatic cancer HA22T/VGH cell line, which constitutively expresses activated nuclear factor-kappaB (NF-kB), waschosen as a model to examine the antitumor activity of curcumin, also in relationship to its possible influences on theactivation of the transcription factor and on the expression of the inhibitory of apoptosis proteins (IAPs) and of other NFkBtarget genes. Curcumin exerted cell growth inhibitory and apoptotic effects, related, at least part, to free radicalgeneration and mainly dependent on caspase-9 and -3 activation. The combination of curcumin with cisplatin resulted ina synergistic antitumor activity and that with doxorubicin in additivity or sub-additivity. Curcumin exerted biphasicchanges in the levels of NF-kB, with an increase at 8 h after its administration and a decrease at 16 h. For thecombinations of curcumin with the other drugs, the levels of the transcription factor were lower than those predictedfrom the effects of the single agents, especially with a blunting of the remarkable increases in NF-kB activation inducedby doxorubicin. Except for Bcl-2, the HA22T/VGH cells expressed different other genes, including the IAPs, implicatedin cell proliferation and survival. Curcumin determined early changes in COX-2 and c-myc mRNAs, which were downregulated,and in livin mRNA, which was up-regulated. Later it decreased Bcl-XL mRNA and increased Bcl-XS andc-IAP-2 mRNAs. Cisplatin and doxorubicin exerted distinct effects on gene expression. The cytotoxic interactionsbetween curcumin and these agents were accompanied by synergistic (in particular with cisplatin) or additive effects ofdecrease in the expression of different genes, including c-myc, Bcl-XL, c-IAP-2, NAIP and XIAP. However, thecombinations attenuated also certain influences on mRNA expression of the single agents, like, for example, the increasesin Bcl-Xs given by curcumin and doxorubicin. Overall, the effects of the drugs, alone or in combination, on tumor cellgrowth, cell death and gene expression did not show a simple relationship to the relative influences on NF-kB activation,inferring that they can be due also to other mechanisms.
Lingua originaleEnglish
pagine (da-a)53-65
Numero di pagine13
RivistaCancer Letters
Volume224
Stato di pubblicazionePublished - 2005

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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