Modulation Of Molecular Markers By Polymeric Black Tea Polyphenols (PBPs) In Tobacco Carcinogen Induced Lung Carcinogenesis In A/J Mice

Rasika HUDLIKAR, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre(TMC), Kharghar, Navi Mumbai, India
THORAT R. 2 , KANNAN S. 3 , INGLE A. 2 , DESAI S. 4 , MARU G. 1 , MAHIMKAR M. 1

1 Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre(TMC), Kharghar, Navi Mumbai-410210, India
2 Laboratory Animal Facility, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre (TMC), Kharghar, Navi Mumbai-410210, India
3 Epidemiology and Clinical Trial Unit (ECTU), Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre (TMC), Kharghar, Navi Mumbai-410210, India
4 Department of Pathology, Tata Memorial Hospital, Tata Memorial Centre (TMC), Parel, Mumbai-400012, India.

Purpose: Chemoprevention with phytochemicals is an evolving approach in cancer management. We evaluated chemopreventive-efficacy (anti-initiation and anti-promotion) of predominant polyphenols in black tea, polymeric black tea polyphenols (PBPs) in experimental lung carcinogenesis.
 
Methods: Pretreatment of black tea derived PBPs (0.75,1.5,3%) were employed to study the dose-related anti-initiation effects (expression and activity of XMEs) on B(a)P induced lung carcinogenesis in A/J mice using western blotting and BPDE-DNA adducts using immunohistochemical staining.  Anti-promotion mechanism of 1.5% PBPs on B(a)P and NNK induced lung lesions was investigated by decrease in macroscopic and microscopic lung tumor incidence and/or multiplicity and/or delay in the latency period. Inflammation, cell proliferation and apoptosis markers along with signaling kinases like p38, Akt and their phosphorylated forms were studied using immunoblotting and immunohistochemical staining at 4th,10th and18th week post-carcinogen treatment.
 
Results:  Pretreatment with 1.5 and 3% black tea derived PBPs showed significant down-regulation in carcinogen induced expression and activity of isoforms of phase I (CYP1A1 and 1A2) and up-regulation in phase II (GST mu, pi and alpha) enzymes with decrease in BPDE-DNA adducts; Administration of PBPs decreased the macroscopic and microscopic lung tumor multiplicity significantly. Although, tumor incidence and latency period remains unaffected, histopathological evaluation of lung at 6, 10 and 18 weeks post-carcinogen treatment decreased tumor multiplicity which correlated with different molecular markers. Along with anti-inflammatory action (reduced Cox-2), PBPs down-regulated proliferation (diminished PCNA and Bcl-2) and enhanced apoptosis (increased Bax) potentially through p38 and Akt phosphorylation.
 
Conclusions: Chemoprevention by PBPs through modulation of xenobiotic metabolizing enzymes (anti-initiation) and inhibition of carcinogen induced inflammation, cellular proliferation and induction of apoptosis possibly via modulation of signaling kinases (anti-promotion). Evaluation of such compounds in multiple organs will further help in monitoring the chemopreventive clinical trials.
 
Funding: Authors thank TMC and DAE for providing fellowship to RH and supporting the project.