The emerging relationship between metabolism and DNA repair

Figures & data

Figure 1. The interplay between DDR and cellular metabolism. The players of the different DDR pathways can differentially regulate the energetic metabolism. ATM was shown to upregulate the expression of glucose transporters and to promote the activity of G6PD and the PPP, leading also to the synthesis of nucleotide and production of glutathione to counteract ROS. ATM can also promote mitochondrial metabolism by increasing the activity of complex I. p53 instead, can inhibit glucose uptake and glycolysis, favouring the activity of PPP. Furthermore, p53 can induce the synthesis of nucleotide and glutathione and increase mitochondrial activity promoting the assembly of complex IV. DNA-PK is able to induce lipogenesis and FAS whilst downregulating the number of mitochondria during ageing. Amongst HR genes, BRCA1 can inhibit the activity of glycolysis to favour mitochondrial metabolism through the TCA cycle; whilst in the context of MMR, MLH1 is important for the regulation of complex I activity and the inhibition of ROS production. Loss of NER activity (ERCC1-/-) leads to inhibition of glycolysis favouring the re-routing of glucose towards PPP. Finally, in the context of BER, loss of XRCC1 is associated with increased expression of AA-transporters and upregulation of serine biosynthesis; whilst increased PARP activity leads to compromising of glycolysis. GLUT – glucose transporters; AA – amino acids transporters; G6PD – glucose-6-phosphate dehydrogenase; PPP – pentose phosphate pathway; ROS – reactive oxygen species; TCA cycle – tricarboxylic acid cycle; ETC – electron transport chain; DDR – DNA damage response; HR – homologous recombination; MMR – mismatch repair; NER – nucleotide excision repair; BER – base excision repair 

Table 1. Therapeutic agents targeting metabolism for cancer treatment; either approved, in clinical trials, or undergoing preclinical research

DNA Damage Repair Pathway (Gene)	Altered Metabolic Pathway	Drug	Target	Phase
DSBR (BRCA1, ATM, P53)	TCA Cycle Metabolism	Enasidenib (AG-221)	Mutant IDH1	Approved for AML [135]
		Ivosidenib (AG-120)	Mutant IDH2	Approved for AML [135]
		CB–839	Glutaminase (GLS)	Phase I clinical trials [118]
		CPI–613	KGDHC	Phase I and II clinical trials [118]
MMR (MLH1), DSBR (BRCA1), DSBR (ATM)	OXPHOS	Parthenolide	NADPH oxidase	Preclinical [58]
		VLX600	Iron chelator	Preclinical [87]
		Tigecycline	Inhibits mitochondrial protein translation	Preclinical [87]
		Metformin	NADH dehydrogenase	Preclincal, Phase I-IV clinical trials [136]
		IACS-010759	NADH dehydrogenase	Preclincal, Phase I clinical trials [108]
NER (ERCC1, XPG), DSBR (ATM)	Pentose Phosphate Pathway	Polydatin	G6PD inhibitor	Preclinical [110,111]
DSBR (BRCA1, ATM, P53)	Glycolysis	WZB117	GLUT inhibitor	Preclinical [87,113]
		Phloretin	GLUT inhibitor	Preclinical [113]
		Lonidamine	Hexokinase2 inhibitor	Phase II clinical trials [113]
		Koningic Acid	GAPDH inhibitor	Preclinical [113]
		Oxamate	Lactate dehydrogenase inhibitor	Preclinical [113]
		Dichloroacetate	Pyruvate dehydrogenase inhibitor	Phase I clinical trials [113]
		Alpelisib	PI3K Inhibitor	Approved for Breast Cancer [115]
		Idelalisib	PI3K Inhibitor	Approved for CLL [116]
DSBR (DNA-PK, BRCA1)	Fatty acid synthesis	TVB-2640	Fatty acid synthase inhibitor	Phase II clinical trials [121]
		ND-646	Acetyl-CoA carboxylase inhibitor	Preclinical [122,123]

Golub D, Iyengar N, Dogra S, et al. Mutant Isocitrate Dehydrogenase Inhibitors as Targeted Cancer Therapeutics. Front Oncol. 2019;9:417.

 PubMed Web of Science ®Google Scholar

Anderson NM, Mucka P, Kern JG, et al. The emerging role and targetability of the TCA cycle in cancer metabolism. Protein Cell. 2018;9(2):216–237.

 PubMed Web of Science ®Google Scholar

Rashid S, Freitas MO, Cucchi D, et al. MLH1 deficiency leads to deregulated mitochondrial metabolism. Cell Death Dis. 2019;10(11):795.

 PubMedGoogle Scholar

Kanakkanthara A, Kurmi K, Ekstrom TL, et al. BRCA1 Deficiency Upregulates NNMT, Which Reprograms Metabolism and Sensitizes Ovarian Cancer Cells to Mitochondrial Metabolic Targeting Agents. Cancer Res. 2019;79(23):5920–5929.

 PubMed Web of Science ®Google Scholar

Heckman-Stoddard BM, DeCensi A, Sahasrabuddhe VV, et al. Repurposing metformin for the prevention of cancer and cancer recurrence. Diabetologia. 2017;60(9):1639–1647.

 PubMed Web of Science ®Google Scholar

Molina JR, Sun Y, Protopopova M, et al. An inhibitor of oxidative phosphorylation exploits cancer vulnerability. Nat Med. 2018;24(7):1036–1046. .

 PubMed Web of Science ®Google Scholar

Jiang J, Chen Y, Dong T, et al. Polydatin inhibits hepatocellular carcinoma via the AKT/STAT3-FOXO1 signaling pathway. Oncol Lett. 2019;17(5):4505.

 PubMed Web of Science ®Google Scholar

Mele L, La Noce M, Paino F, et al. Glucose-6-phosphate dehydrogenase blockade potentiates tyrosine kinase inhibitor effect on breast cancer cells through autophagy perturbation. J Exp Clin Cancer Res. 2019;38(1):160.

 PubMedGoogle Scholar

Abdel-Wahab AF, Mahmoud W, Al-Harizy RM. Targeting glucose metabolism to suppress cancer progression: prospective of anti-glycolytic cancer therapy. Pharmacol Res. 2019;150:104511.

 PubMed Web of Science ®Google Scholar

André F, Ciruelos E, Rubovszky G, et al. Alpelisib for PIK3CA-Mutated, Hormone Receptor–Positive Advanced Breast Cancer. N Engl J Med. 2019;380(20):1929–1940.

 PubMed Web of Science ®Google Scholar

Markham A. . Idelalisib: first Global Approval. Drugs. 2014;74(14):1701–1707.

 PubMed Web of Science ®Google Scholar

Punekar S, Cho DC. Novel Therapeutics Affecting Metabolic Pathways. Am Soc Clin Oncol Educ Book.2019 (39):e79–e87.

 Google Scholar

Li E-Q, Zhao W, Zhang C, et al. Synthesis and anti-cancer activity of ND-646 and its derivatives as acetyl-CoA carboxylase 1 inhibitors. Eur J Pharm Sci. 2019;137:105010.

 PubMed Web of Science ®Google Scholar

Svensson RU, Parker SJ, Eichner LJ, et al. Inhibition of acetyl-CoA carboxylase suppresses fatty acid synthesis and tumor growth of non-small-cell lung cancer in preclinical models. Nat Med. 2016;22(10):1108–1119.

 PubMed Web of Science ®Google Scholar