Preclinical evaluation of Meriva (a formulation of curcumin) as a putative agent for chemoprevention of lung cancer

Curcumin, a naturally occurring dietary polyphenol, has been investigated for several years for its role in chemoprevention of cancer. There are emerging evidences that curcumin may have a potential role in prevention and treatment of lung cancer. Curcumin in its natural form is poorly absorbed, extensively metabolised and rapidly excreted. Meriva, a phospholipid formulation of curcumin, promises to enhance its bioavaibility. The work described in this thesis investigates whether Meriva offers pharmacokinetic advantage over unformulated curcumin, elucidate a possible mechanism of action for curcumin and determine efficacy of Meriva in vivo using xenograft model of lung cancer. Meriva offered superior curcumin and curcumin metabolites levels in mice plasma and lungs at two different dose levels (high and low). The levels were 5-16 fold higher for Meriva as compared to unformulated curcumin. A HPLC-UV method developed and validated for simultaneous quantification of curcumin and metabolites was found to reliable and reproducible. In vitro, a 3D organotypic model was used to demonstrate important role stromal components, namely fibroblasts, play in cell invasion and metastasis. Curcumin treatment of organotypic cultures significantly inhibited tumour cell invasion. Curcumin also modulated a number of key proteins in HGF/MET signalling axis. Nude mice were administered either control diet or diet supplemented with 0.226% w/w Meriva one week after A549:MRC5 (1:5) cell inoculation. Meriva significantly inhibited tumour growth versus control (p<0.05). The expression of p53, Ki-67 and cleaved caspase-3 which were significantly altered following Meriva intervention. These results together provide evidence that Meriva at a clinical relevant dose regime may be investigated in prevention and treatment of lung cancer.