S. No. Phytochemicals In vitro and in-vivo model Mechanism of action Reference
1
Apigenin
HNSCC: CAL-27, SCC-15, FaDu. OSCC: SCC-25, HaCaT. HSC-3, HN-30 & HN-8. ↑apoptosis, ↓pEGFR, ↓pErbB2, ↓Akt, ↓Erk1/2. ┴proliferation, ↑apoptosis, ↓cyclin D1 and E1. ↓CSCs marker, ↓CD44, ↓NANOG, ↓CD105. (Masuelli et al., 2011) (Maggioni et al., 2013) (Ketkaew et al., 2017)
2 Anthocyanin OSCC: SCC15, Tca8113 ┴Invasion & migration, ↑ apoptosis, ↑Pyroptosis, ↑ NLRP3, ↑caspase-1, ↑IL-1β. (Yue et al., 2019)
3
Baicalein
SCC 4 HSC 3 Cal 27 HONE1 & HK1/Akata, C666-1, CNE1. CNE1, CNE2 ↑apoptosis, ↑ Bax, ↓ Ca2+, ↓ Bcl-2, ↑Cytochrome c, ↑ p53, ↑Caspase 3 & Caspase 9. ┴proliferation, ↑AhR, ↓pRb, ↓Cyclin D1, ↓CDK4, induces G1 phase arrest. ↑autophagy, ↑ROS, ↑Beclin, ↑LC3 II, ↑Bax, ↓p62, ↓Bcl-2. ┴proliferation of NPC, ┴ EBNA1 promoter, ┴SP1, ↓tumor growth of EBV positive. ┴Growth, ┴proliferation, ↑apoptosis, Arrest cell cycle at G0/G1, ↑Bax, ↑Bad, ↓Bcl-Xl, ↓Mcl-1, ↑Caspase 3,8,9. (Lin et al., 2007) (Cheng et al., 2012) (Li et al., 2017a) (Zhang et al., 2018) (Guo et al., 2019)
4 Betulinic acid HNSCC: SCC9, SCC25. ↑apoptosis, ↓Bax. (Thurnher et al., 2003)
5
Biochanin A
SCC 15, SCC25. FaDu ┴MAPK, ↓pERK, ↓pAkt, ┴Akt pathway. Cytotoxic, ┴Migration, ↑apoptosis, ↓P38, ↓MAPK, ↓Akt, ↑FasL, ↑Caspase 3, 8, ↓Bcl-2, ↓Bcl-Xl, ↑PARP, ↑Bad, ↓MMP-2, ↓MMP-9. (Johnson et al., 2010a) (Cho et al., 2017)
6
Caffeic acid phenethyl ester SAS, OEC-M1 Detroit 562 Cytotoxic, Arrest G2/M phase. ┴Growth, ↑apoptosis, arrest cell cycle at G0/G1 phase. (Lee et al., 2005) (Dziedzic et al., 2017)
7
Curcumin
HNSCC: CCL23, CAL27, UM-SCC1, UMSCC-14A, In-vivo. FaDu, CAL27. OSCC: SCC25 Hep-2, SCC-15, FaDu, In-vivo. CAL-27 ┴Growth, ↓NF-KB, ↓P-IKB-α, ↓Cyclin D1. ┴Growth, ↑apoptosis, ↓migration, ↓angiogenesis, target SIRT1. ┴invasiveness, ┴EMT, ↓MMP-2, ↓MMP-9, ↑p53, ↑E-Cadherin. ┴Growth, ↑apoptosis, Induce G2/M arrest, ┴ATM/Chk2/p53. ↓CaMKK2, ↓invasion and colony forming ability. (LoTempio et al., 2005) (Hu et al., 2015) (Lee et al., 2015a) (Hu et al., 2017) (Nanjappa et al., 2017)
8
Emodin Aloe-emodin FaDu, OEC-1. KB NPC-TW 039 & NPC-TW 076, Detroit 562, SCC4, (CE81T/VGH & CE 48T/VGH). ┴invasion, ┴migration, ↓vimentin, ┴TWIST1, ↓E-cadherin, ┴β-catenin, ┴ Akt. ↓proliferation, Arrest G2/M phase, ↑ALP. ↑apoptosis, ↑Caspase-3, ↑Bax, decreases ↓Bcl-XL, ↑Ca2+, ↑ROS, arrest G2/M phase, ↑cyclins B1. (Way et al., 2014) (Xiao et al., 2007) (Lin et al., 2010)
9
Galangin
WSU-HN4, HN4 & HN13. TU 212, HEP-2, In-vivo. NPC ┴proliferation, ↑apoptosis, ↓colony formation, arrest G0/G1 phase, ↓cyclin-D1, ↓AKT-P, ↓mTOR, ↓Bcl-2, ↓Bcl-xl, ↑Bax, ↑caspase-3. ┴proliferation, ┴migration, ↑apoptosis, ↑autophagy, ↓PI3K, ↓AKT, ↓NF-KB, ↓mTOR, ↓Ki67, ↑LC3-II, ↑Beclin 1, ↑caspase 3, ↑caspase 9. ↑apoptosis, arrest S-phase, ┴PI3K-Akt. (Zhu et al., 2014) (Wang et al., 2017) (Lee et al., 2018)
10
Gallic acid
HSC-2 SCC-4, SCC-9 NPC-BM1 ↑apoptosis, ↑ROS, ↓reduced glutathione. ┴proliferation, ┴migration, ┴invasion, ↑E-Cadherin, ↓Col.1A1, ↓HIF-α. ┴invasion, ┴AP-1/ETS-1, ↓MMP-1, ↓p38 MAPK, ↓c-Jun, ↓c-Fos, ↑TIMP-1. (Schuck et al., 2013) (Guimaraes et al., 2016) (Pang et al., 2017)
11
Genistein
HN-4 SCC-25 SCC15, SCC25. Tongue carcinoma cell lines ↑apoptosis, ┴invasion, ↓c-erbB2, downregulates ↓MMP-2, ↓MMP-9, ↓NF-κB. ┴growth, ┴COX-2, G2/M phase arrest. ┴proliferation, ┴MAPK, ↓phosphorylation of ERK &Akt. ┴proliferation, ┴viability, ↓migration, ↓vitronectin, ↓OCT4, ↓Survivin. (Alhasan et al., 2001) (Ye et al., 2004) (Johnson et al., 2010b) (Ardito et al., 2018)
12
Gingerol 6-Gingerol. Ginger extract KB, SCC 4. SCC25, Cal27, FaDu. Cytotoxic, ↑apoptosis, Arrest G2 & S phase. ┴proliferation, ↑apoptosis, Radiosensitizer, ↓colony formation, ↓Survivin. (Kapoor et al., 2016) (Kotowski et al., 2018)
13
Green tea Polyph -enols EGCG FaDu Hep-2 SNU-899, KB, SNU-1086, SCC VII/SF, FaDu, In-vivo. FaDu, KB, SNU899, AM-HN9. ┴HGF, ┴invasion, ┴metastasis, ↓MMP-9, ↓uPA activity, decrease ↓ERK, ↓Akt. ↑apoptosis, ┴growth, ┴proliferation, ↓telomerase, ↑caspase-3. ↑apoptosis through ATM/p53, ↑NAG-1, ┴tumor formation. ↑apoptosis, ┴growth, ↓β-Catenin. (Lim et al., 2008) (Wang et al., 2009) (Kang et al., 2013) (Shin et al., 2016)
14
Guggulsterone
HN5, SCC-4, FaDu PCI-37a, UM-22b SCC-4, HSC-2 ↑apoptosis, ┴growth, S-phase arrest, ↑c-Jun N-terminal kinase, ↓Akt pathway. ↑apoptosis, ┴invasion, ↓HIF-1α, ↓phosphotyrosine, ↓STAT-3. ↑apoptosis, ↑2A (PP2A), ↓PI3-Kinase/Akt, ↓survivin, ↓cyclinsD1, ↓c-myc. (Shishodia et al., 2007) (Leeman-Neill et al., 2009) (Macha et al., 2011)
15
Honokiol
Cal 33, 1483 (OSCC). HSC-3, HSC-4. SAS. SCC1, SCC5, OSC-19, FaDu. SAS, OECM-1. ┴EGFR, ↓MAPK, ↓Akt, ↓STAT-3, ↓cyclin D1, ↓Bcl-xL. ┴growth, ┴proliferation, ↑apoptosis. ↑apoptosis, ┴EMT, ┴CD44, ┴Wnt/β-catenin, ↑cleaved caspase3, ↑GSK-3α/β, ↓TCF-4, ↓slug, ↓snail, ↓ c-myc, ↓cyclin D1, ↓Bcl-2. ┴viability, ↑apoptosis, ↓EGFR, ↓mTOR. ┴sphere formation, ┴growth, ↑apoptosis, ┴migration, ↑Bax/Bcl-2, ↑caspase 3, ┴IL-6, ↓JAK2/STAT3, ↓Akt, ↓Erk, ↓PCNA, ↓CD31. (Leeman-Neill et al., 2010) (Chen et al., 2011) (Yao et al., 2013) (Singh et al., 2015) (Huang et al., 2016)
16
Indole-3-Carbinol
CNE-1, In-vivo CNE-2 Hep-2, In-vivo CNE-2, 5-8F (NPC) In-vivo CNE2 NPC, In-vivo ┴growth, ┴proliferation, ↑apoptosis, ↓malondialdehyde, ↑SOD, ↑Glutathione peroxidase, ↑caspase3, 9. ↑apoptosis, ↓XIAP, ↓c-IAP1, ↓Survivin, ↑omi, ↑smac, ↑cyto-c, ↑Fas/FasL, ↑ MAPK. ┴growth, ┴proliferation, ↑apoptosis, ↓P-PDK1, ↓(PI3K) P110α, β, ↓P-Akt, ↓PI3K ClassIII, ↓Akt, ↓P-c-Raf, ↓GSK-3β. ┴growth, ↑G1 phase arrest, ↓cyclin D1, ↓CDK4, ↓CDK6, ↓pRb. ┴growth, ↓proliferation, ↑apoptosis, ↓PI3K/Akt. (Zhu et al., 2010) (Xu et al., 2011) (Wang et al., 2013) (Chen et al., 2013c) (Mao et al., 2014)
17
Phenyisothocyan -ate HSC-3 HN22 SAS Cal-27, FaDu, SCC4, SCC9, SCC15, SCC-25, Tu138, In-vivo ↑apoptosis, ↓Cyclin E, ↓Cdk2, ↑p53, ↑p21, ↑p17, ↓Bcl-2, ↑Bax, ↑Bid. ↑apoptosis, ↑DR5, ↑Caspase-3, 8, ↑Bid, ↓EGF, ┴invasion, ↑TIMP-1, 2, ↓MMP-2, 9, ↓phosphorylation of AKT, PI3K(P38), EGFR, PDK1, ↑MAPK, ↓NF-Kβ, ↑phosphorylation of P-38, JNK & ERK. ┴growth, ↑ROS, Nuclear translocation of p53, p21, Arrest G1/S phase, ↑p53, ↑8-oxo-dG, ↓Ki-67. (Chen et al., 2012a) (Huong et al., 2012) (Chen et al., 2013a) (Lam-Ubol et al., 2018)
18
Benzylisothiocya -nate 1483, UM-22B SCC-9, In-vivo Antiproliferative, Cytotoxic, ↑Caspase 3, ↑PARP cleavage, ↑p44/42 MAPK. ┴viability, ↑apoptosis, ┴growth, ┴invasion, ↓S100A4, ↓MMP-9, ↑PUMA. (Lui et al., 2003) (Ma et al., 2019)
19
Sulforaphane
Tca 8113KB, YD-10B, In-vivo. YD8, YD10B, YD15. SAS, GNM (OSCC). UMSCC-22A, Cal33, UMSCC-1, UPCI: SCC090, In-vivo. ┴proliferation, ┴HIF-1α, ↑ERK, ↑JNK, ↓VEGF. Antiproliferative, ↑apoptosis, ↓COX-2, ↓Bcl-2. Anti-metastatic, ┴migration, ┴invasion, ↓MMP-2, ↓MMP-9. ↓self-renewal, ↓CD44, ↓ALDH, ↑tumor suppressive miR200c. ↓migration, ↓invasion, ↓clonogenicity, ↓growth, ↑NRF2, ↑GCLC, ↓STAT3. (Yao et al., 2008) (Cho et al., 2009) (Jee et al., 2011) (Liu et al., 2017) (Bauman et al., 2016)
20
Kaempferol
SCC 4 FaDu, PCI-13, PCI-15B, In-vivo. Antimetastatic, ┴migration, ┴invasion, ↓MMP-2, ↓TIMP-2, ↓ERK1/2, ↓AP1, ↓c-Jun. ┴viability, ↑apoptosis. (Lin et al., 2013) (Swanson et al., 2014)
21 Lupeol HEp-2, UPCI: SCC-131 ┴viability, ↑apoptosis, ↑p53, Arrest G1 phase, ↑Bax, ↑Caspase 3, ↑CDKN2A, ┴Cyclin D, ┴ki67. (Bhattacharyya et al., 2017)
22
Luteolin
SCC-25 In-vivo Xenograft mouse model. Regulates DNA damage, Phosphorylation of ATM & H2AX in DNA repair pathway. ┴P300 lysine acetyl transferase activity, ↑p53, ↓migration. (Tjioe et al., 2016) (Selvi et al., 2015)
23
Lycopene
In-vivo: DMBA induce carcinogenesis model. KB-1 In-vivo: NQO induce carcinogenesis model. FaDu, Cal 27 ↑Antioxidants, ↓tumor growth, ↑GSH, ↑GPx, ↑GST, ↑GR. ┴proliferation, ↑Gap junction, ↑Connexin-43. ↓proliferation, ┴invasion, ↓PCNA, ↑E-cadherin, ↑β-catenin. ┴proliferation, ┴invasion, ↑apoptosis, ↓PKB, ↓MAPK, ↑Bax, ↑caspase 3, ↑cleaved caspase 9, ↓Bcl-2. (Bhuvaneswari et al., 2001) (Livny et al., 2002) (El-Rouby, 2011) (Ye et al., 2016)
24
Myricetin
UT-SCC 42B SCC 25 Hypermethylation of genes RAR-β & MGMT frequently hypermethylated. ┴proliferation, ┴migration, Cytostatic, ↓Cyclin D1, Arrest G2/M phase, ↓P-Akt, ↓ERK1/2. (Paluszczak et al., 2011) (Maggioni et al., 2014)
25 Naringenin SCC-25 ┴proliferation, ┴migration, ↑apoptosis, ↓Cyclin D1, Arrest G0/G1 phase, ↓ERK1/2, ↑Caspase 3, 9. (Maggioni et al., 2014)
26
Polydatin
CNE Hep-2, AMC-HN-8 In-vivo. CAL 27 ┴viability, ↑apoptosis, ↓P-Akt, ↑CHOP, ↑UPR, ↑ROS, ↑Cytochrome-c, ↑Caspase 3, 4. ┴proliferation, ↑apoptosis, ┴tumor growth, ┴PDGF-B, ┴P-Akt, ↓ki67, ↓Bcl-2, ↑Bax. ↓CYP1A1, ↓HSP-90, ↓Aryl hydrocarbon receptor (AHR). (Liu et al., 2011) (Li et al., 2017b) (Martano et al., 2018)
27
Pseudolaric Acid B
HN 22, HSC 3, Ca9.22, HSC 4
┴viability, ↑apoptosis via death receptor (DR5), ↑Cleaved Caspase-8.
(Choi et al., 2019)
28
Querceitin
SAS, OECM-1. FaDu, HSC-3. HSC-3, TW206, FaDu, HSC-3 ↓ALDH1, ↓migration, ↓twist, ↓N-cadherin, ↓vimentin. ┴growth, ↑apoptosis, ↑FOXO1, G2 phase arrest, ┴EGFR/Akt. ┴Colony growth, ┴migration, ┴invasion, ↓MMP-2, ↓MMP-9. (Chang et al., 2013) (Huang et al., 2013) (Chan et al., 2016)
29
Resveratrol
UM SCC-22B FaDu, Cal 27, Det 562, In-vivo. SG, SAS or OECM1 In-vivo. SCC- 9 FaDu. HN3, FaDu, SCC 4. HSC-4, FaDu. CAL 27, CAR cell. CNE-1 NPC, In-vivo. CAL-27, SCC15, SCC 25. CNE-1, CNE-2, HONE1, C666-1. ↑apoptosis, ↑Cox-2, ↑P53, ↑ERK1/2, ↑binding of p53 to p21 promoter. Antiproliferative, ↑apoptosis, ┴tumor growth, S phase arrest, ↑Brac 1, ↑γ-H2AX focci, ↑Caspase 3,8. ↓self-renewal, ↓stemness, ↓invasiveness ↓growth, ↓ALDH1, ↓CD44, ↓Oct 4, ↓Nanog, ↓Nestin, ↓EMT, ↓Slug, ↓ZEB1, ↓N-Cadherin, ↓E-Cadherin, ↓Vimentin. ┴MMP 9, ┴motility, ┴migration, ┴ phosphorylation of c-JNK, ↓JNK1/2, ↓ERK1/2. ↑apoptosis, ↑Radiosensitiviy, Arrest G2/M. ┴proliferation, ↑Apoptosis, ┴invasion, Radiosensitizer, ┴STAT3, ↑SOCS-1, ┴JAK2, Arrest sub-G1 phase, ↓Cyclin D1, ↓VEGF, ↓MMP 2, ↓MMP9, ↓Survivin, ↓Bcl-2, ↓Bcl-Xl, ↓IAP-1, ↑PARP cleavage, ↑Caspase 3 & 9. ┴growth, ↑Radio &chemosentivity, ┴invasion, ↑REG III regenerating genes. ↑apoptosis, ↑autophagy, Induces ↑Atg5, ↑Atg12, ↑Beclin-1, ↑LC3-II, increases ↑Caspase 9, ↑P-AMPK, ↑PI3K class III, ↑Bax, ↑Bax, ↓P-AKT, ↓P-mTOR, ↓Rubicon, ↓P-Bad, ↓Bcl-2, ↓Bcl-Xl. ↑apoptosis, ↑Radiosensitivity, ┴tumor growth, ┴colony formation, G1 phase arrest, ↓E2F1, ↓P-Akt. ↓viability, ↑apoptosis, ┴EMT, ┴migration, ↑Bad, ↑Bax, ↑Caspase 3, 9, ↑E-Cadherin, ↑PARP, ↑APAP-1, ↑Cytochrome-c, ↓Bcl-2, ↓Bcl-Xl, ↓N-Cadherin, ↓slug, ↓snail, ↓Zeb1, ↓Smad2/3. ┴proliferation, ┴PCNA, ┴Ki67, ↓Survivin, ↑Caspase-3, ↑cleaved Caspase 9. (Lin et al., 2008) (Tyagi et al., 2011) (Hu et al., 2012) (Lin et al., 2015) (Shao et al., 2015) (Baek et al., 2016) (Mikami et al., 2016) (Chang et al., 2017) (Tan et al., 2017) (Kim et al., 2018) (Xiong et al., 2019)
30
Rosmarinic acid
UM-SCC-6, UM-SCC-10B
┴growth, ┴migration, ┴EGFR signaling, ┴viability, ┴ROS, ↓PI3K/Akt, ↓MAPK/ERK.
(Tumur et al., 2015)
31 Salvianolic acid B JHU-022, JHU-013. ↑apoptosis, ↓COX-2, ↓PGE2, increase ↑Caspase 3, ↑p53, ↑Bcl-2, ↑Bcl-xL. (Hao et al., 2009)
32
Silibilin
Hep-2 SAS, OECM1 ↓viability, Synergy with Arsenic trioxide,↑ROS, ↑Caspase-3, ↓survivin. ↓ALDH1, ↓CD133, ↑microRNA-494, ↓tumor growth, ↓Bmi/ADAM10. (Yang et al., 2013) (Chang et al., 2015)
33
Thymoquinone
T28, In-vivo. SASVO3, In-vivo. ↑apoptosis, ↓P38β MAPK, ↓COX-2, ↑P-p53, ↑Bad, ↑Bid. ↑apoptosis, ↑autophagy ↓tumor growth, ↑Bax, ↑Caspase 9, ↑Autophagic vacuoles, ↑autophagosome and ↑LC-31. (Abdelfadil et al., 2013) (Chu et al., 2014)
34 Ursolic acid CAL27, CAR cells ↑apoptosis, ↓P-Akt, ↓BAD, increases ↑ROS, ↑Caspase 3,9, ↑Bad, ↑Bax, ↓Bcl-2, ↓Bcl-xl. (Chen et al., 2018)
35
Ellagic acid
DMBA-induced carcinogenesis model. DMBA-induced carcinogenesis model. DMBA-induced carcinogenesis model. ↑apoptosis, NF-κB, ↓Wnt, ↓Fz, ↓Dvl-2, ↓GSK3β, ↓β-catenin, ┴NF-κB, ↓IKKβ, ↑Bax. ┴VEGF/VEGFR2, PI3K/AKT & MAPK signalling, ┴HIF1-α, ↓PI3K, ↓PDK-1, ↓P-Akt, ↓mTOR, ↓P-ERK, ↓P-JNK, ↓HDAC-6. ↑plasma & buccal TBRAS, ↓oxidative damage, ↑antioxidants enzymes, ↑antioxidants, ↓oxidants. (Anitha et al., 2013) (Arulmozhi et al., 2013) (Arulmozhi et al., 2013)
36
Ferulic acid
DMBA induced carcinogenesis model. DMBA induced carcinogenesis model. Antiproliferative, ┴tumor formation, ↑apoptosis, ↓p53, ↓Bcl-2. Anti-cell proliferative, ┴tumor formation, ↓PCNA, ↓Cyclin D1. (Balakrishnan et al., 2010) (Prabhakar et al., 2012)
37
Hesperetin
DMBA induced carcinogenesis model. DMBA induced carcinogenesis model. ┴tumor formation, ┴proliferation, ↑apoptosis, ↑Bax, downregulates ↓PCNA, ↓Bcl-2, ↑antioxidants enzymes. Antiproliferative, ↑apoptosis, ↑mutant p53, ↑Caspase-3,9, ↑cyclin D. (Babukumar et al., 2017). (Babukumar et al., 2020)