Inhibition of acetyl-CoA carboxylase suppresses fatty acid synthesis and tumor growth of non-small c

Nd 646 treatment of a549 cells did not significantly

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ND-646 treatment of A549 cells did not significantly alter cholesterol synthesis, demonstrating that ACC inhibition does not impact acetyl-CoA utilization by non-FASyn pathways (Supplementary Fig. 3 a ). Collectively, these metabolic flux data demonstrate that, analogous to ACC1 genetic deletion, ACC inhibition by ND-646 results in potent inhibition of FASyn and depletes cellular levels of fatty acids in NSCLC cells. Svensson et al. Page 6 Nat Med . Author manuscript; available in PMC 2017 March 19. Author Manuscript Author Manuscript Author Manuscript Author Manuscript
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ND-646 inhibits proliferation and is cytotoxic in NSCLC cells— ND-646 markedly inhibited proliferation (Supplementary Fig. 3 b,c ) and viability (Supplementary Fig. 3 d ) of A549, H157, H1355 and H460 NSCLC cells, demonstrating that ACC inhibition impairs cancer cell growth, consistent with results from the genetic deletion of ACC1 and consistent with previous studies 16,17 . Additionally, the ability of ND-646 to inhibit proliferation was enhanced when cells were cultured in media containing delipidated FBS (Fig. 3d). Notably, ND-646 treatment of ACC1 -KO A549 and H157 clones grown in regular or delipidated FBS did not further affect cellular viability (Fig. 3 e ), and cotreatment of A549 cells with ND-646 and palmitate restored viability and completely rescued the antiproliferative effects of ACC inhibition (Fig. 3 f,g and Supplementary Fig. 3 e ). Palmitate rescue was also recapitulated in H460 cells (Supplementary Fig. 3 f ) and palmitate had no effect on the ability of ND-646 to inhibit ACC because co-treatment with ND-646 resulted in loss of P-ACC detection, demonstrating that ACC is effectively inhibited in palmitate- rescued cells (Supplementary Fig. 3 g ). These data demonstrate the specificity of ND-646 for ACC inhibition, as palmitate would not be expected to rescue any unexpected off target effects of ND-646. ND-646 treatment of A549 cells led to induction of apoptosis (Fig. 3 h ) and ER stress (Supplementary Fig. 3 h ). ACC inhibition led to increased phosphorylation of the α -subunit of the eukaryotic translation initiation factor 2 on serine 51 (P-EIF2 α S51 ) and also increased the expression of CHOP. Co-treatment of A549 cells with ND-646 and palmitate completely rescued the effects of ND-646 on ER stress and apoptosis (Fig. 3 i ). Taken together, these data suggest that the anti-proliferative effects of ND-646 are due to inhibition of FASyn and depletion of cellular fatty acids ND-646 inhibits FASyn and tumor growth in NSCLC xenografts— Our pharmacokinetic studies suggested that ND-646 would be more efficacious when delivered at multiple daily doses. Thus, to explore the impact of chronic ND-646 treatment on NSCLC tumor growth and to determine the efficacy of twice-daily dosing, we treated athymic nude mice bearing established A549 subcutaneous tumors orally with either vehicle twice daily (BID), 25 mg/kg ND-646 once daily (QD), 25 mg/kg ND-646 BID or 50 mg/kg ND-646 QD for 31 days (Fig. 4 a ). ND-646 at 25 mg/kg QD was ineffective at inhibiting tumor growth.
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  • Winter '19
  • Robert S Kiss
  • Fatty acid metabolism, Nat Med, FASyn

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