Comparison of oxaliplatin‐ and curcumin‐mediated antiproliferative effects in colorectal cell lines

Abstract

Colorectal cancer remains a leading cause of cancer death worldwide, despite markedly improved response rates to current systemic therapies. Oxaliplatin either alone or incorporated into 5-fluorouracil/leucovorin regimes has resulted in increased survival rates, particularly with regards to metastatic colorectal carcinoma. The chemopreventive polyphenol curcumin, which is currently in clinical trial, has been advocated for use in colorectal cancer either singly or in combination with chemotherapeutic drugs. In this study, the antiproliferative capacity of both compounds was compared in HCEC (normal-derived), HT29 (p53 mutant adenocarcinoma) and HCT116 (p53wt adenocarcinoma) colorectal cell lines to determine whether effects were cell-type specific at pharmacologically achievable doses, and whether the combination resulted in enhanced efficacy. Both oxaliplatin and curcumin displayed marked antiproliferative capacity at therapeutic concentrations in the two tumor cell lines. Order of sensitivity to oxaliplatin was HCT116>HT29>HCEC, whereas order of sensitivity to curcumin was HT29>HCT116>HCEC. HCT116 cells underwent induction of G2/M arrest in response to both oxaliplatin (irreversible) and curcumin (reversible). Apoptosis was induced by both agents, and up to 16-fold induction of p53 protein was observed in response to the combination. Antiproliferative effects in HT29 cells were largely cell cycle independent, and were mediated by induction of apoptosis. Effects were greatly enhanced in both cell lines when agents were combined. This study provides further evidence that curcumin may be of use in therapeutic regimes directed against colorectal cancer, and suggests that in combination with oxaliplatin it may enhance efficacy of the latter in both p53wt and p53 mutant colorectal tumors. ' 2007 Wiley-Liss, Inc.

Curcumin Inhibits Human Non-small Cell Lung Cancer A549 Cell Proliferation Through Regulation of Bcl-2/Bax and Cytochrome C

“…Curcumin can promote inhibition or arrest cell cycle at all stages through increasing p53 and p21 expression (Jaiswal et al, 2002). In addition, curcumin inhibits cancer cell growth by stimulating the activation of casepase-3, casepase-7 and caspase-8 (Notarbartolo et al, 2005;Howells et al, 2007). Furthermore, curcumin affects cancer cell proliferation by suppressing TNF-induced NF-κB-dependent gene products (COX-2, cyclin-D, c-myc) (Aggarwal et al, 2006).…”

Curcumin induces apoptosis-independent death in oesophageal cancer cells

“…However, novel formulations and metabolism inhibitors attempting to optimise the pharmacological potency of curcumin have gained attention, such as the use of piperine, nanoparticles, liposomes, phospholipid complexes and structurally altered derivatives and analogues that dramatically improve the biological activity of curcumin (Shoba et al, 1998;Mishra et al, 2005;Liu et al, 2006;Anand et al, 2007;Li et al, 2007;Mosley et al, 2007). Combination studies so far in both in vitro and in vivo have highlighted promising combinations of curcumin with oxaliplatin (Howells et al, 2007;Li et al, 2007;Patel et al, 2008) and paclitaxel (Aggarwal et al, 2005), suggesting there is a very definite potential for curcumin to be used as part of mainstream clinical regimes.…”

Cancer chemoprevention and chemotherapy: Dietary polyphenols and signalling pathways

“…In this regard, treatment of Caco-2 cells (human colon adenocarcinoma cells) with a phenolic acid such as ellagic acid, or punicalagin, hydrolysable tannin which rendered ellagic acid in the culture medium to enter into the cell and that can be found in strawberries, walnuts and pomegranate, provoked S cell cycle arrest, preceded by increased expression of cyclin E and decreased expression of cyclins A and B1 [79]. G2/M cell cycle arrest, down-regulation of the cyclin A and upregulation of the CDK inhibitor p21 and Cdc2 have also been observed by curcumin in human colon and bladder cancer cells [80,81] and, interestingly, anthocyanins, predominant phenolic compounds in berry extracts, disrupted the cell cycle by increasing p21 expression [82] similar to ellagic acid and quercetin which also increased p53 levels [83]. Additionally, piceatannol, a grape and wine polyphenol, prevented human melanoma cell proliferation by arresting the cell cycle at G2 phase and down-regulating cyclins A, E and B1 [84], and 29-OH flavanone, which also led to G2/M phase accumulation, reduced cyclin B, cyclin D and Cdc2 in human lung A459 cancer cells [85].…”