Table 2.

Apoptotic- and autophagy-inducing effects of luteolin based on in vitro studies. Arrows designate up (↑), and downregulation (↓) of the molecules.

Type of Cancer	Cell Lines	Effects	Mechanisms	Concentration	References
Osteosarcoma	MG63 and U2OS	Induces apoptosis	↓ chemoresistance to doxorubicin and cisplatin, ↓ cancer cell viability and proliferation, ↑ miR-384 level, ↓ PTN expression, ↓ PTN/b-catenin/MDR1 signaling axis, ↑ doxorubicin response in doxorubicin-resistant MG63/DOX cells, ↑ miR-384 in exosomes derived from luteolin-treated MG63 cells	0, 1, 2, 3, 4, 5 μM	[126]
Colon	HCT116	Induces apoptosis and autophagy	↓ cell migration, ↓ HIF-1α-dependent transcription, ↓ G1 and G2/M cells, ↑ cells in S phase, ↑ apoptotic frequency, ↑ necrotic cell death, ↑ LC3-II, Luteolin treatment reversed increase of CD44 and CD47	2.5–200 μM	[127]
	SW620	Induces apoptosis and autophagy	↓ viability and proliferation of cancer cells, ↑ HO-1, ↑ SOD2, ↓ Bcl-2, ↑ Bax, ↑ Cleaved caspase-3, ↑ PARP cleavage, ↑ Beclin-1, ↑ Atg5, ↑ LC3B-I/II, ↑ LC3B-I, reversal of the epithelial-mesenchymal transition, ↑ FOXO3a, ↑ apoptosis, ↑ TUNEL-positive cells, ↑ p21, ↑ phospho-ERK1/2, phospho-JNK1/2 and phospho-p38 expression	0.2, 5, 10, 20, 50, 100 μM	[47]
	HT-29, SNU-407	Induces apoptosis	↓ viability of cancer cells, ↑ Bax, ↑active caspase-9 and 3, ↓ Bcl-2, ↑ protein expression of GCLc, GSS, catalase and HO-1, ↑ DNA demethylation, ↑ mRNA expression of Nrf2	0, 5, 10, 20, 30, 40, 50, 60, 70 and 80 μM	[128]
Breast	MCF-7	Induces apoptosis	↑ Cytotoxicity for cancer cell lines, ↑ anti-breast cancer activity of L-ZnONPs was mediated by polo-like kinase 1 (PLK1) proteins (In silico studies)	2.5, 5, 10, 20, and 40 µM concentrations of luteolin, zinc oxide nanoparticles, and L-ZnONPs.	[129]
	MCF7-TamR	Induces apoptosis	Cell cycle arrest at the G2/M phase, ↓ mitochondrial membrane potential, ↓ PI3K/AKT/mTOR signaling pathway, ↑ p27, ↑ cleaved-Caspase 7, 8, 9, and poly (ADP-ribose) polymerase (PARP), ↑BAX and BIM, ↓ Bcl-2, ↓ p-p85, p-AKT, and p-mTOR, ↑ MLL3 and Mono methylation of H3K4, ↑ K-Ras, H-Ras, and N-Ras mRNA	0, 10, 20, and 30 μM	[130]
	MDA-MB231	Induces apoptosis and autophagy	↓ cell migration, ↓ HIF-1α-dependent transcription, ↓ G1 and G2/M cells, ↑ cells in S phase, ↑ apoptotic frequency, ↑ necrotic cell death, ↑ LC3-II, Luteolin treatment reversed increase of CD44 and CD47	2.5–200 μM	[127]
	MDA-MB-453 and MCF-7	Induces apoptosis	↓ cells viability, ↑ apoptosis frequency, ↑ Bax, ↓ Bcl-2, ↓ Vimentin, ↓ Zeb1 ↓ N-cadherin, ↑ E-cadherin, ↑ miR-203 level, ↓ Ras/Raf/MEK/ERK signaling	0, 5, 10 and 20 μM	[131]
Lung	NCI-H1975 and NCI-H1650	Induces apoptosis	↓ proliferation of cancer cells, ↓ LIMK1 activity, ↑ cell cycle arrest at G1 phase, ↑ apoptosis frequency, ↓ cyclin D1 and ↓ cyclin D3, ↑ Bax, ↑ cleaved caspase 3, ↑ cleaved caspase-7, ↑ cleaved PARP expression, ↓ caspase-3, ↓ caspase-7, ↓ p-LIMK1/2 and p-cofilin	0, 5, 10, 20 or 40 μmol/L	[38]
	BEAS-2B, KRAS-mutant human lung cell lines H358, H460, H2122, and A549	Induces apoptosis	↓ growth and proliferation of cancer cells, ↓ MUC1-C and PD-L1, ↓ p-STAT1 or STAT3, ↑ IL-2, ↓ IFN-γ-induced PD-L1 expression	Apigenin and luteolin—0, 10, 20, 30, 40, 50 μM	[132]
Non-Small Cell Lung	A549 and NCI–H1975	Induces apoptosis	↓ cancer cell viability, ↑ apoptosis, ↑ caspase-8, caspase-3 and caspase-9, ↑ DR5 expression, ↓ mitochondrial length, ↑ Drp1 from the cytoplasm onto mitochondria, ↑p- Drp1(Serine616 residue), ↑ cytochrome c release from mitochondria, ↑ cytochrome c in the cytosolic fraction, ↓ mitochondrial cytochrome c content	0, 5, 10, 20, 30, 40 μM Luteolin + TRAIL (25 ng/mL)	[133]
	A549 and H460	Induces apoptosis	↓ proliferation of cancer cells, ↑ apoptosis frequency, ↑ P53 and P21, ↓ MDM4, ↑ Caspase 3 and 9	0, 5, 10, 20, 30, 40, 60, 80, and 100 µM	[81]
Gastric	NCI-N87 and MKN28, Hs-746T	Induces apoptosis	↓ cell proliferation, invasion, and migration of cancer cells, reversed EMT by shrinking the cytoskeleton, ↑ E-cadherin, ↓N-cadherin, ↓ vimentin, ↓ Snail, ↓ β-catenin levels, ↓ Notch1, ↓ cyclin-D1, ↓ Hes-1	0, 10, 20 and 30 μM	[134]
	MKN45, MKN28, BGC823, AGS and SGC7901	Induces apoptosis	↓ Proliferation and invasiveness of cancer cells, ↑ apoptosis frequency, ↓ MMP9, ↓ p-cMet, ↓ p-Akt, ↓ p-ERK, ↑ cleaved caspase-3 and PARP-1	0–80 μM	[135]
Pancreatic	MIAPaCa2, PANC1, BxPC3, KP4, HuPT3, PK1, PA-TU-8988T, TCCPAN2 and AsPC1	Induces apoptosis	↓ cancer cell proliferation, ↓ STAT3 activity, ↓ phospho-AMPK (Thr172), ↓ phospho-p38 MAPK (Thr180/Tyr182), ↓ phospho-STAT3 (Tyr 705), ↑ phospho-GSK3β (Ser 9), ↓ DPYD expression	25 or 50 μM	[136]
	SW1990 andAspc-1	Induces apoptosis	↓ cell proliferation, ↓ BCL-2, ↑ apoptotic frequency of cells, ↑ loss of mitochondrial membrane potential, ↑ activation of pro caspase-3 and PARP	50 μM and 100 μM	[137]
Hepatocellular	HepG2 (p53 wild type) and Hep3B (p53 null type)	Induces apoptosis	↓ cancer cell numbers, ↑ Protein levels of PARP cleaved, ↓ PCNA, ↓ catalase protein levels, ↑ mRNA levels of both Bip and spliced Xbp-1, ↑ p53 protein levels, ↑ p21 gene expression↓ TAp63 mRNA levels, ↑ LC3-II, ↓ p62	0, 5, 10 μM	[138]
	SK-Hep-1 and AML12	Induces apoptosis	↓viability of cancer cells, ↑ apoptotic cell population, ↑ sub-G1 population, ↑ cleaved-caspase 8, -9 and -3, cleaved-PARP, ↓ XIAP, ↓ Mcl-1, ↓ cleaved Bid, ↓ p- AKT	20, 40, 60 and 80 μM	[139]
	SMMC-7721	Induces apoptosis	↑ G0/G1-phase arrest, ↓ % age of cell s in G2/M-phase, ↑ %age of early apoptosis, late apoptosis, and total apoptosis, ↑ caspase 8, ↓ Bcl-2, ↑ intracellular autophagosomes, ↑ LC3B ↑ BECN1 mRNA, ↑ conversion of LC3B-I to LC3B-II, ↑ Beclin1	0, 12.5, 25, 50, 100, and 200 µM	[140]
	HepG2, HLF, and HAK-1B	Induces apoptosis	↓ cancer cell proliferation, ↑ cleaved caspase-8, caspase-3, caspase-7 and PARP, ↑ Fas/CD95 expression, ↓ p-STAT3s, ↓ Tyr705-phosphorylated STAT3, ↓ Ser727-phosphorylated STAT3, ↓ cyclin D1, ↓ survivin, ↓ Bcl-xL, ↓ VEGF, ↓ Tyr-phosphorylated CDK5	0, 10, 20, 50 μM	[141]
Liver	HepG2	Induces apoptosis	↑ frequency inhibiting HepG2 cell proliferation than free luteolin, ↑ enhance the uptake of drugs by cells, ↓ Bcl-2 and ↑ LDH	Luteolin-loaded PD-L1 targeted stealth PLGA/Liposomes (5.0 mg luteolin)	[142]
	MHCC97-H, HepG2,PLC/PRF/5, Hep3B, HEK293	Induces apoptosis	↑ inhibitory impact of VVIL-24 on liver cancer cells viability, ↑ IL-24 gene expression, ↑ apoptosis frequency, ↑ cleaved PARP, cleaved caspase-3, cleaved caspase-8, ↓ procaspase-3 and procaspase-8, ↓ XIAP	VV-IL-24 (4 MOI) and Luteolin (5 µg/mL)	[143]
	Huh7 andHep3B	Induces apoptosis and autophagy	↓ cell viability, ↑ apoptotic bodies, ↑ LC3-II, ↓ p62, ↑ DR5, ↑ cleaved caspase-3 and cleaved caspase-8	0, 5, 10 and 20 µM	[144]
Bladder	T24, 5637 with a p53 mutation and RT-4 with wild-type p53	Induces apoptosis	↑ G2/M arrest, ↑ p21Waf1/Cip1, ↑ p27Kip1, ↓ cyclin A and D1, ↓ phospho(p)-Akt, ↓ phospho(p)-p70S6K, ↓ phospho(p)-S6, ↑ TRX1, ↓ Intracellular ROS	0, 1, 10, 25, 50, 100 µM	[145]
Colorectal	HCT 116 and SW 620 (Oxaliplatin resistant)	Induces apoptosis	↑ Nrf2, ↑ NQO1, ↑ HO-1, ↑ GST α1/2, ↓ reduced glutathione, ↑ chemotherapeutic potential of cisplatin, oxaliplatin and doxorubicin	1, 5 and 10 μM	[146]
Choriocarcinoma	JAR and JEG-3	Induces apoptosis	↓ Proliferation and viability of cancer cells ↑ apoptosis frequency, ↑ loss of mitochondrial membrane potential, ↓ p-AKT, ↓ p-P70S6K, ↑p-GSK3β, ↓ AKT, ↑ERK1/2, ↓ PI3K/AKT and ERK1/2 signaling pathways ↓ SREBP1, ↓ SREBP2, ↓ SCAP mRNAs, ↓ p-mTOR, ↓ lipogenic genes	0, 5, 10 and 20 μM	[147]
Cervical	HeLa	Induces apoptosis	↓ methylation of crucial tumor suppressor genes like APC, BRCA1, CDH13, CDKN2, MGMT, MLH1, RARB, RASSF1 and TIMP3, ↓ global DNA methylation, ↓ DNMT activity, ↓ Histone deacetylation activity, modifies the expression of various chromatin-modifying enzymes, ↓histone methyl transferases such as ASH1L, WHSC1, SU2V40H1, ↓ HAT activity	5, 10, and 20 µM	[148]