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ABSTRACT
Flaxseed is a rich source of the plant lignan secoisolariciresinol diglucoside (SDG), which is metabolized into mammalian lignans enterodiol (ED) and enterolactone (EL) in the digestive tract. The anticancer properties of these lignans have been demonstrated for various cancer types, but have not been studied for lung cancer. In this study, we investigated the anticancer effects of EL for several nonsmall cell lung cancer (NSCLC) cell lines of various genetic backgrounds. EL inhibited the growth of A549, H441, and H520 lung cancer cells in concentration- and time-dependent manners. The antiproliferative effects of EL for lung cancer cells were not due to enhanced cell death, but rather due to G1-phase cell cycle arrest. Molecular studies revealed that EL decreased mRNA or protein expression levels of the G1-phase promoters cyclin D1, cyclin E, cyclin-dependent kinases (CDK)-2, -4, and -6, and p-cdc25A; decreased phosphorylated retinoblastoma (p-pRb) protein levels; and simultaneously increased levels of p21WAF1/CIP1, a negative regulator of the G1 phase. The results suggest that EL inhibits the growth of NSCLC cell lines by downregulating G1-phase cyclins and CDKs, and upregulating p21WAF1/CIP1, which leads to G1-phase cell cycle arrest. Therefore, EL may hold promise as an adjuvant treatment for lung cancer therapy.
Declaration of interest
S. Chikara, K. Lindsey, H. Dhillon, S. Mamidi, J. Kittilson, M. Christofidou-Solomidou, and K.M. Reindl have declared that they have no conflict of interest. Dr. Christofidou-Solomidou has patents No. PCT/US14/41636 and No. PCT/US15/22501 pending and has a founder's equity position in LignaMed, LLC.
Acknowledgment
The authors would like to thank Dr. Devendra Chikara for editing this paper.
Funding
This work was supported by grants from National Science Foundation (No. HRD-0811239) and National Institute of Health (No. P30 GM103332-01) from the National Center for Research Resources.