NKT inhibits proliferation and sensitizes

Abstract

Despite multiple efforts in prevention and treatment, lung cancer remains one the world leading causes of death. Non-small-cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases with relatively high rate of LKB1 and KRAS mutations. In this study, we utilize the lung adenocarcinoma A549 together with the adriamycin (ADR)-resistant A549/ADR cell line in the effort of looking for the novel effective strategy in combating against this type of cancer. By using MTT assay, colony formation assay and western blotting, we showed for the first time that NKT, a major constituent of grapefruit, activated AMPK in A549 and A549/ADR leading to the inhibition of cell growth by downregulating mTOR and P70S6K phosphorylation. Moreover, cell cycle analysis revealed another possible proliferation inhibiting effect of NKT by arresting cell cycle at G1 phase. In addition to AMPK activation and cell cycle arrest, NKT alone treatment also showed promising effect in KRAS-mutant A549 and A549/ADR by inhibiting the oncogenic AKT and ERK pathways. As the combined therapy has shown great potential in cancer treatment by targeting different pathways at the same time, we sought to examine the effect of NKT in combination with ADR on A549 and A549/ADR. The in vitro results show the synergistic effect of NKT and ADR by significantly inducing apoptosis in both cell lines. Our in vivo data also further confirmed this synergism without any possible systemic side effects. Altogether, these results demonstrate that NKT is a promising anticancer agent in KRAS mutant and LKB1 mutant NSCLC.