The Mismatch Repair System Modulates Curcumin Sensitivity through Induction of DNA Strand Breaks and Activation of G2-M Checkpoint

Abstract

The highly conserved mismatch (MMR) repair system corrects postreplicative errors and modulates cellular responses to genotoxic agents. Here, we show that the MMR system strongly influences cellular sensitivity to curcumin. Compared with MMR-proficient cells, isogenically matched MMR-deficient cells displayed enhanced sensitivity to curcumin. Similarly, cells suppressed for MLH1 or MSH2 expression by RNA interference displayed increased curcumin sensitivity. Curcumin treatment generated comparable levels of reactive oxygen species and the mutagenic adduct 8-oxo-guanine in MMR-proficient and MMR-deficient cells; however, accumulation of γH2AX foci, a marker for DNA double-strand breaks (DSB), occurred only in MMRpositive cells in response to curcumin treatment. Additionally, MMR-positive cells showed activation of Chk1 and induction of G 2 -M cell cycle checkpoint following curcumin treatment and inhibition of Chk1 by UCN-01 abrogated Chk1 activation and heightened apoptosis in MMR-proficient cells. These results indicate that curcumin triggers the accumulation of DNA DSB and induction of a checkpoint response through a MMR-dependent mechanism. Conversely, in MMR-compromised cells, curcumin-induced DSB is significantly blunted, and as a result, cells fail to undergo cell cycle arrest, enter mitosis, and die through mitotic catastrophe. The results have potential therapeutic value, especially in the treatment of tumors with compromised MMR function. Mol Cancer Ther; 9(3); 558-68. ©2010 AACR.

Carboplatin resistant human laryngeal carcinoma cells are cross resistant to curcumin due to reduced curcumin accumulation

“…The induction of DNA damage that we observed in HEp-2 and 7T cells following the treatment with curcumin is in agreement with those previously reported, despite differences in the type of cells and experimental conditions used (Cao et al, 2006;Huang et al, 2011;Jiang et al, 2010;Lin et al, 2008;Lopez-Lazaro et al, 2007;Su et al, 2006;Urbina-Cano et al, 2006). Although we have expected that more oxidative DNA damage (like oxidized purines) would appear in HEp-2 and 7T cells because of ROS induction, strand breaks were predominant and correlated with cytotoxicity.…”

“…However, minor oxidative DNA damage was found only in HEp-2 cells, and this could be the result of enhanced early ROS induction found in these cells. Presence of DNA strand breaks after curcumin treatment could be explained by the work of Jiang et al (2010). They showed the role of mismatch repair system in curcumin induction of DNA double strand breaks at the place of mutagenic adduct 8-oxo guanine.…”

Effect of curcumin on irradiated and estrogen-transformed human breast cell lines

“…Curcumin reversibly arrests normal mammary epitelial cells at G 0 /G 1 phases. However, apoptosis by curcumin was reported in mammary epithelial carcinoma cells at the G 2 phase of cell cycle (14)(15)(16)(17)(18)(19).…”

“…The DNA damage includes double-strand breaks (DSB), single strand breaks, base damage, bulky adducts, intra/interstrand cross links, and breakdown of replication fork lesions where one of the key proteins in the base excision repair pathway is the Poly adenosine diphosphate ribose polymerase-1 (PARP-1) (6,19,(32)(33)(34). PARP-1 is a 116-kDa nuclear protein that appears to be involved in DNA repair predominantly in response to environmental stress (32,33).…”

Non-Steroidal Anti-Inflammatory Drugs, DNA Repair and Cancer

“…Microarray analysis of human lung cancer cells after curcumin treatment saw an upregulation of GADD45 and GADD153 gene expression (Saha et al, 2010) and microarray analysis has also shown an up-regulation of GADD45 by curcumin treatment in a human breast cancer cell line (Ramachandran et al, 2005). It has recently been proposed that DNA MMR may play a role in the cellular response to curcumin (Jiang et al, 2010): DNA MMR proficient cells showed a greater accumulation of double strand breaks (DSB) upon curcumin treatment compared to MMR deficient cells suggesting that DSB formation induced by curcumin is primarily a DNA MMR-dependent process; further to this, curcumin was reported to activate ATM/Chk1 and cause cell-cycle arrest and apoptosis in human pancreatic cancer cells. DNA MMR proficient cells showed activation of Chk1 and induction of the G(2)-M cell cycle checkpoint (Jiang et al, 2010) suggesting that the curcumin induced checkpoint response may be a DNA MMR dependent mechanism.…”