Abstract
Starving tumor cells by restricting nutrient sources is a promising strategy for combating cancer. Because both berberine and cinnamaldehyde can activate AMP-activated protein kinase (AMPK, a sensor of cellular energy status), we investigated whether the combination of berberine and cinnamaldehyde could synergistically prevent lung carcinogenesis through tumor cell starvation. Urethane treatment induced lung carcinogenesis in mice, downregulated AMPK and mammalian target of rapamycin (mTOR) while upregulating aquaporin-1 (AQP-1) and nuclear factor kappa B (NF-κB). Together, berberine and cinnamaldehyde reduced mouse susceptibility to urethane-induced lung carcinogenesis, and reversed the urethane-induced AMPK, mTOR, AQP-1, and NF-κB expression patterns. In vitro, berberine and cinnamaldehyde together induced A549 cell apoptosis, prevented cell proliferation, autophagy, and wound healing, upregulated AMPK, and downregulated AQP-1. The effects of the combined treatment were reduced by rapamycin (a mTOR inhibitor) or HgCL2 (an AQP inhibitor), but not Z-VAD-FMK (a caspase inhibitor). The berberine/cinnamaldehyde combination also prevented A549 cell substance permeability and decreased intracellular ATP concentrations. These results suggest the combination of berberine and cinnamaldehyde limited both primary and adaptive nutrient acquisition by lung tumors via AMPK-reduced AQP-1 expression, which ultimately starved the tumor cells.