Table 8.

The Effects of the metabolic interventions on the epithelial ovarian cancer chemoresistant cell lines and the metabolic interventions that alter the chemosensitization properties: reports from in vitro studies

Human Ovarian Cell Types	Intervention (Dose/Duration)	Major findings											Interpretation	References
		Glycolytic-related findings				OXPHOS-related findings				Oncological outcomes
		Glycolytic enzymes	Lactate	Basal ECAR	Others	OXPHOS enzymes	Basal OCR	ROS	Others	Proliferation	Apoptosis	Viability
-Chemoresistant ovarian carcinoma (C200)	-Glucose-free media (48 h)			↑↑	↑↑ glycolytic capacity		↑↑		↑↑ max. respiration	↑↑			-Chemoresistant cells had higher metabolic state than chemosensitive cells, and could shift toward OXPHOS or glycolysis under stress conditions.	[51]
									↑↑ ATP
-Chemosensitive ovarian carcinoma (A2780) (control)	-Glucose-free media + pyruvate (1 mM, 48 h)			↑↑	↑↑ glycolytic capacity		↑↑		↑↑ max. respiration	↑↑
									↑↑ ATP
	-Glucose supplement (10 mM, 48 h)			↑↑	↔ glycolytic capacity		↑↑		↑↑ max. respiration
									↑ ATP
	-2-DG (100-200 mM, 48 h)											↑↑
	-Oligomycin (0.1-2 µM, 48 h)											↔
-Chemosensitive ovarian carcinoma (A2780)	-2-DG (6.25, 25, 100 mM, 48 h)			↓↓	↑↑ glycolytic capacity		↔		↑↑ max. respiration	↓		↔	-Chemosensitive cells might use glycolysis as the main pathway and could increase the metabolic state when using non-toxic concentration of cisplatin.
	-Oligomycin (0.31-1.25 µM, 48 h)			↑↑			↓↓
	-Cisplatin (1 µM, 24-48 h)			↑↑			↑↑
-Chemoresistant HGSC (PEO4)	-Cisplatin (10 mM, 48 h) + oligomycin (0.1 mM, 48 h)											↓↓	-Resistant cells had the ability to shift metabolism type, and decreased viability when exposed to a combined OXPHOS inhibitor with cisplatin.
	-Cisplatin (control)
	-Cisplatin (10 mM, 48 h) + 2-DG (100 mM, 48 h)											↓↓
	-Cisplatin (control)
-Chemoresistant serous ovarian carcinoma (C200)	-2-DG (6.25, 25, 100 mM, 48 h)			↓↓			↑↑			↓
	-Oligomycin (0.31-1.25 µM, 48 h)			↑↑			↓↓
	-Cisplatin (10 mM, 48 h) + oligomycin (0.1 mM, 48 h)											↓↓
	-Cisplatin (control)
	-Cisplatin (10 mM, 48 h) + 2-DG (100 mM, 48 h)											↔
	-Cisplatin (control)
-Platinum resistant HGSC (PEA2)	-PEA2 and PEA1 in low-glucose medium (glucose 1 g/L, 72 h)											↑	-Platinum-resistant cells were more tolerate to glucose deprivation.	[36]
-Platinum sensitive HGSC (PEA1) (control)
-Platinum sensitive HGSC (PEA1)	-TRAP1 silencing (siRNA transfection, 72 h)	↔ PFK		↔	↔ glycolytic capacity		↑	↑	↑ BEC index				-Increasing OXPHOS by TRAP1 silencing or OXPHOS inducer could induce platinum resistant in platinum sensitive HGSC.
	-Cisplatin (20 µM, 24 h)										↑↑	↓
	-Cisplatin + OXPHOS inducer (FCCP 1.2 µM, 24 h)										↓	↑↑
	-Cisplatin (control)
	-Cisplatin + TRAP1 silencing										↓	↑
	-Cisplatin (control)
	-Cisplatin + TRAP1 silencing + metformin											↓
	-Cisplatin + TRAP1 silencing (control)
-Platinum resistant HGSC (PEA2)	-TRAP1 silencing (siRNA transfection, 72 h)								↔ BEC index				-Using complex I inhibitor, metformin, could induce chemosensitivity in platinum resistant HGSC.
	-Cisplatin (40 µM, 24 h)										↑	↓
	-Metformin (10 mM, 24 h)										↔	↓
	-Cisplatin + metformin										↑	↓↓
-Cisplatin resistant carcinoma (SKOV3/DDP)	-2-DG (10 mM, 24 h)											↑	-Cisplatin resistant cells had higher OXPHOS, were less sensitive to glucose deprivation, but use of glycolysis or anti-apoptotic inhibitors could increase cell apoptosis.	[52]
-Cisplatin sensitive carcinoma (SKOV3) (control)	-OXPHOS inducer (FCCP 2.5 µM, 24 h)						↑		↑ respiratory reserve
-Cisplatin sensitive ovarian carcinoma (SKOV3)	-Glucose-free media (24 h)											↓
	-Bcl-2 inhibitor (ABT737 10 µM, 24 h)				↓ HIF-1α		↔		↔ ATP		↔
	-Cisplatin (6 µg/mL, 24 h)						↓↓		↓↓ ATP		↑↑
	-Bcl-2 inhibitor + cisplatin						↓		↓↓ ATP		↑↑
-Cisplatin resistant ovarian carcinoma (SKOV3/DDP)	-Glucose deprivation (glucose-free medium)											↓
	-Glucose deprivation + 2-DG (10 mM, 24 h)											↓
	-Glucose deprivation (control)
	-Bcl-2 inhibitor (ABT737 10 µM, 24 h)				↓ HIF-1α		↓		↓↓ ATP		↑↑
	-Cisplatin (6 µg/mL, 24 h)						↔		↓↓ ATP		↑↑
	-Bcl-2 inhibitor + cisplatin						↓↓		↓↓ ATP		↑↑
	-Bcl-2 inhibitor + 2-DG	↓ HK2			↓ Glut1	↓ PDHB		↑			↑
					↓ HIF-1α	↓ IDH1
-Chemosensitive ovarian carcinoma (HeyA8, OV2008)	-PFKFB3 inhibitor (PFK158, 10-15 µM, 30 min)		↓		↓ glucose uptake								-Inhibition of PFKFB3 could resensitize chemoresistant cells.	[19]
	-PFKFB3 inhibitor (PFK158, 10 µM, 24 h)										↔
	-CBP (77 µM, 24 h) or PTX (0.2 µM, 24 h)										↔
	-PFKFB3 inhibitor + CBP or PTX										↑↑
-Chemoresistant ovarian carcinoma (C13, HeyA8MDR)	-PFKFB3 inhibitor (PFK158, 10-15 µM, 30 min)		↓		↓ glucose uptake
	-PFKFB3 inhibitor (PFK158, 10 µM, 24 h)										↔
	-CBP (453 µM, 24 h) or PTX (3.59 µM, 24 h)										↔
	-PFKFB3 inhibitor + CBP or PTX										↑↑
-Ovarian carcinoma (SKOV3, OVCAR3)	-MPC1 inhibitor (20 µM, 1 week			↑	↑ glucose uptake				↓ mt-pyruvate			↑	-MPC1 knockout promoted glycolysis and induced chemoresistance.	[48]
									↓ ATP
	-MPC1 inhibitor + docetaxel (10 nM, 2 weeks)											↑
-Ovarian carcinoma (SKOV3, COC1)	-BM-MSC-CM (miR-1180 abundant 24 h)	↑ HK2		↑		↑ PDK1			↑ ATP	↑		↑	-MiR-1180 induced glycolysis and chemoresistance.	[17]
	-Standard medium (control)	↑ PKM2
		↑ LDHA
	-Glycolytic inducer (oligomycin 2 mg/mL, 24 h)			↑
	-BM-MSC-CM + cisplatin (0.5 mg/L, 24 h)									↑		↑
	-Cisplatin (control)
	-Cisplatin (0.5 mg/L, 24 h) + oligomycin (2 mg/mL, 24 h)									↑		↑
	-Cisplatin (control)
	-Anti-miR-1180 in BM-MSC-CM + cisplatin (0.5 mg/L, 40 min for ECAR, 5 days for proliferation)			↓					↓ ATP	↓		↓
	-control miRNA in BM-MSC-CM + cisplatin (control)
-Ovarian carcinoma (433, A2780, SKOV3, OVCAR3)	-Pim1 overexpression (72 h)	↓ PGK1, PGAM1, ENO1, PKM, LDHA	↑	↑	↓ GLUT1		↓			↑		↑	-Inhibition of Pim1 reduced glycolysis and induced chemosensitization to cisplatin.	[65]
	-Pim1 silencing (shPim1/siPim1 transfection, 72 h)		↓	↓	↔ HIF-1α		↑			↓		↓
	-Pim1 inhibitor (4 nM) + cisplatin (1 µM), 48 h											↓
	-Cisplatin alone (control)
-Ovarian carcinoma (CP90, OV90)	-MICU1 silencing (siRNA transfection, 48-96 h)		↓			↓ p-PDH	↑	↑	↑ complex III	↓	↑	↓	-Silencing MICU1 induced OXPHOS and enhanced cytotoxic effects of cisplatin in ovarian cancer cells.	[45]
	-MICU1 silencing + cisplatin (10-20 µM)/topotecan (5-10 µM)/PTX (10-25 µM)/doxorubicin (1-2 µM), 48 h		↔			↑ PDH		↑		↓
	-Cisplatin/topotecan/paclitaxel/doxorubicin (control)					↑ PDH
-Normal ovarian epithelial cells (OSE)	-MICU overexpression (1 µg)		↑			↑ p-PDH	↓			↑			-MICU overexpression induced glycolysis and chemoresistance in normal ovarian cells.	[45]
	-MICU overexpression (1 µg) + cisplatin (2.5 µM), 48 h					↓ PDH
	-Cisplatin (control)
-OCCC (RMG2, JHOC5)	-Knockdown HNF1ß (sh-HNF1ß transfection)	↓ HK1	↓		↑ 3-PG			↑	↑ citrate, 2-oxoglutarate				-Silencing HNF-1ß caused OCCC cells impaired adaptation to hypoxic conditions, increased resistance to glucose deprivation, and enhanced cytotoxicity of cisplatin in hypoxic conditions.	[33]
		↓ LDHA			↑ PEP				↔ ATP
					↑ pyruvate				↓ fumarate, malate
					↓ MCT4
	-Hypoxic condition (2% O2, 24/48 h)											↑
	-Knockdown HNF-1ß + Hypoxic condition											↓
	-Control + hypoxic condition
	-Knockdown HNF-1ß + glucose-free medium (24/48 h)											↑
	-Cisplatin (20-80 µM + sh-HNF1ß in hypoxic condition											↓↓
	-Cisplatin treated in control cells in hypoxic condition
-Cisplatin sensitive serous carcinoma (A2780, PEO1)	-Cisplatin (50 µM, 24 h)				↓ HIF-1α			↑			↑	↑	-Cisplatin downregulated HIF-1α and induced apoptosis only in cisplatin sensitive cells.	[54]
	-NAC (5 mM, 24 h) + cisplatin (20 µM, 72 h)										↓
	-Cisplatin (control)												-HIF-1α knockdown could resensitize cisplatin-resistant cells.
-Cisplatin resistant serous carcinoma (A2780/CP, PEO4)	-Cisplatin (50 µM, 24 h)	↓ LDHA			↔ HIF-1α			↔			↔	↓
	-HIF-1α silencing (siHIF1 transfection, 72 h) + cisplatin (20 µM, 24 h)							↑			↑
	-Cisplatin (control)

The arrow ↑ or ↓ denotes a significant increase or decrease in the metabolic-related finding or oncological activities with a P value <0.05. The arrow ↑↑ or ↓↓ denotes a significant increase or decrease in the metabolic-related finding or oncological activities with a P value <0.01. Abbreviations: 3-PG; 3-phosphoglycerate, BEC index; BioEnergetic Cellular index, BM-MSC-CM; Condition media of bone marrow-derived mesenchymal stem cells, CBP; carboplatin, ECAR; extracellular acidification rate, ENO; enolase, FCCP; carbonilcyanide p-triflouromethoxyphenylhydrazone, HGSC; high grade serous adenocarcinoma, HIF-1α; hypoxia-induced transcription factor, HK2; Hexokinase 2, HNF-1ß; Hepatocyte nuclear factor 1ß, IDH; isocitrate dehydrogenase, LDH; lactate dehydrogenase, MCT4; Monocarboxylate transporter 4, MICU1; Mitochondrial calcium uptake 1, miR; microRNA, MPC; mitochondrial pyruvate carrier, mt-; mitochondrial, NAC; N-acetyl cysteine, OCCC; Ovarian clear cell carcinoma, OCR; oxygen consumption rate, OXPHOS; oxidative phosphorylation, p-PDH; Phosphorylated-pyruvate dehydrogenase, PDH; pyruvate dehydrogenase, PDK; pyruvate dehydrogenase kinase, PEP; phosphoenolpyruvate, PFK; Phosphofructokinase, PFKFB3; 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3, PGAM; phosphoglycerate mutase, PGK; phosphoglycerate kinase, PKM2; Pyruvate kinase M2, PTX; paclitaxel, ROS; Reactive oxygen species, TRAP-1; Tumor necrosis factor receptor-associated protein 1.