Glucose restriction combined with alpha-lipoic acid decreases cell survivial and migration of hepatocellular carcinoma derived cells

HIDALGO F; FERRETI AC; TONUCCI F; ALMADA E; PARIANI A; LAROCCA MC; FAVRE C

Buenos Aires

Congreso; Reunion cientifica anual conjunta de Sociedades de Biociencias; 2017

Hepatocellular carcinoma (HCC) is the second most lethal cancer,which is in part due to its rapid development of intra and extra hepaticmetastasis. a-Lipoic acid (LA) is clinically used as an antioxidant.Recent studies suggest the use of LA as an anti-cancer agent,associated with activation of AMPK. However, direct evidence of LAcontribution to the treatment of HCC has not been elucidated. Inrecent studies we have demonstrated that AMPK activation signals the survival decrease in HCC cells subjected to glucose starvation(Gs). In this study, we evaluate the effects of LA and Gs on HCC celllines (HepG2/C3A and HuH-7) proliferation, migration and differentiation,and the putative involvement of AMPK signaling pathway.First, we demonstrated that AMPK is activated by LA, and that thisactivation was enhanced when the cells were incubated with Gs. LA0.5 (LA0.5) and 1(LA1) mM decreased the number of viable cellsfrom 48h, and this effect was enhanced in Gs (HuH-7:LA1:67±2*,LA1Gs:45±8*#; C3A:LA1: 66±5*, LA1Gs:46±3*# % vs C). Treatmentwith LA for a longer period of time, drastically reduced clonogeniccapacity in HuH-7 cells. In addition, LA increased the percentageof these cells in G0/G1 by 20% vs C. Wound-healing assayshowed that AMPK activation by 0.5mM LA reduced cell migration,and Gs increased this result (HuH-7:C:339±7*, LA0.5:191±12*,LA0.5Gs:120±15*#; C3A:C:94±4*, LA0.5:62±5*, LA0.5Gs:35±2*#μm). Cell differentiation was evaluated in C3A cells as the capacityof generating canalicular structures typical of epithelial hepatocyticcells. In fact, the number of canalicular structures significantly increasedby LA. In conclusion we found that LA reduces cell proliferationand migration in HCC cells, what parallels the activation ofAMPK, and these antitumor effects are increased by Gs. These findingssupport further studies of LA as a potential therapeutic agentfor HCC treatment, alone and combined with metabolic interventions.*p