Bioactive Plant-Derived Compounds as Novel Perspectives in Oral Cancer Alternative Therapy
Abstract
1. Introduction
2. Investigating the Therapeutic Potential of Bioactive Compounds in Oral Cancer
2.1. Categories, Compounds, and Biological Effects
2.1.1. Phenolic Compounds
2.1.2. Flavonoids and Their Subclasses
2.1.3. Stilbenes and Their Derivatives
2.1.4. Flavonolignans
2.1.5. Quinone and Carotenoids
2.1.6. Alkaloids
2.1.7. Essential Oils
2.1.8. Phenylpropene
2.1.9. Phthalides and Xanthones
2.1.10. Phytosterols
2.1.11. Other Compounds
2.2. Phytotherapeutic Perspectives in Oral Cancer Pathology
2.2.1. Effectiveness of Plants and Natural Compounds Based on the Included Studies
2.2.2. Synergism Between Natural Compounds and Conventional Medicines
2.2.3. Advanced Topical Delivery Systems Used in This Specific Pathology
3. Advanced Methods Used for Bioproducts Cellular Activity Assay
4. Cell Signaling Mechanisms and the Trigger in Therapeutics Approaches
5. Materials and Methods
6. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Scientific Name of the Plant | Family/ Class [175] | Type of Extract | Testing System | Cancer types/Methodology | The Importance of Results | References |
---|---|---|---|---|---|---|
Potentilla discolor | Rosaceae/Magnoliopsida | Methanolic Potentilla discolor extract (MEPD) | in vitro | -Extracellular Matrix (ECM) lines (MC3, YD15) -Trypan blue, Live/dead assay -Western blot: PARP, PUMA, p STAT3 -Immunofluorescence (PUMA, pSTAT3) -Gene transfection: STAT3 overexpression vector | -Highlights the STAT3- PUMA link in mucoepidermoid cancer apoptosis -Suggests MEPD as a complementary therapy -Shows the phytotherapeutic potential in the development of anticancer drugs. | [176] |
Imperata cylindrica | Poaceae/Magnoliopsida | Imperata cylindrica leaf extract (ICL) | in vitro | -ICL methanolic extract (0–640 μg/mL) -SCC-9 vs. NIH/3T3 lines (fibroblasts) -MTT, clonogenic assay, flow cytometry (cell cycle) -DNA electrophoresis | -Demonstrates the potential of ICL against oral cancer -Support for the development of phytotherapeutic therapies with reduced toxicity -Basis for further studies | [177] |
Cardiospermum halicacabum | Sapindaceae/Magnoliopsida | Plant extract | in vitro | -SCC25 cells (1.2 × 104/well), treated with 25–125 μg/mL extract -MTT assay, with cyclophosphamide as positive control | -Suggests plant extract’s potential to fight oral cancer. -Higher doses, combinations with other substances, and in vivo studies need to be studied | [178] |
Scrophularia oxysepala | Scrophulariaceae/Magnoliopsida | Essential oil | in vitro | -Tetrazolium staining method (viability) -Analysis of BAX, BCL2, SMAC, SURVIVIN gene expression by RT-PCR -Observation of cell morphological changes (apoptosis) | -S. oxysepala essential oil as a potential anticancer agent for oral cancer -Requires further investigation (in vivo testing) for clinical validation | [179] |
Padina gymnospora | Dictyotaceae/Phaeophyceae | Seaweed extract | in vitro | -Treatment 15–20 µg/mL/24 h on KB- CHR-8-5 Cells -AO/EB staining for apoptosis morphology -Rh 123 and DCFH-DA for MMP and ROS -Differentially expressed proteins by 2D, MALDI- TOF/TOF -Bio-informatics analysis (STRING, PANTHER) | -Underlines the potential of P. gymnospora as a marine anticancer agent -Identification of the proteins involved helps in the development of future therapies based on natural products -Opens the way to in vivo validation research | [180] |
Pinus densiflora | Pinaceae/Pinopsida | Pinus densiflora leaf essential oil (PLEO) | in vitro | -Steam distillation for extraction PLEO -YD-8 cells treated with 60 µg/mL, 8 h -Proliferation, cytotoxicity assays -ROS measurement, Western blot (caspase, Bcl-2) -Inhibitors (Vitamin E, z-VAD-fmk) to confirm the mechanism | -First study showing the anticancer potential of PLEO on YD-8 -Demonstrates a ROS-caspase pathway for apoptosis -Opens ways for the use of PLEO in the development of oral anticancer therapies | [181] |
Trifolium pratense | Fabaceae/Magnoliopsida | Plant extract | in vitro | -Dried flower powder -MTT test on oral squamous cell carcinoma -Statistical analysis, linear regression for IC50 determination | -Confirms the potential of red clover as an alternative treatment for oral cancer -Further studies on detailed mechanisms are needed -Can be combined with other therapies for increased efficacy | [182] |
Cranberry and grape seed | Ericaceae/Magnoliopsida and Vitaceae/Magnoliopsida | Plant extract | in vitro | -CAL27, SCC25 lines -Phenotypic tests: proliferation, adherence, morphology -Comparison of cranberry vs. grape seed effect -Evaluation of caspases, apoptosis | -Highlights the nutraceutical potential of fruit extracts in oral cancer prevention/treatment -Has dietary and complementary therapy implications -Requires identification of key components and clinical trials | [182] |
Saraca indica bark | Fabaceae/Magnoliopsida | Methanolic extract | in vitro | -Wistar mice, dose groups 250 mg/kg and 500 mg/kg extract -Compared with levamisole and cyclophosphamide -Hematological parameters, DTH reaction, humoral antibodies, leukocytes, serum proteins -14 days | - Provides Saraca indica as a natural immunomodulatory agent -May be useful as an adjuvant in conditions of weakened immunity -Basis for further research on the mechanism and active substances | [183] |
Momordica charantia (Bitter melon) | Cucurbitaceae/Magnoliopsida | Plant extract | in vitro and in vivo | -Laboratory studies (in vitro), animal models (in vivo) -Assessment of effects on proliferation, apoptosis, metabolism, and immune status -Limited epidemiologic analysis to support chemopreventive potential | -Bioactive substance with potential in the prevention/treatment of OSCC -May lead to the development of innovative chemoprevention strategies -Contributes to targeting future clinical research for confirmation of benefits | [184] |
Green tea | Theaceae/Magnoliopsida | Green tea extract (GTE) | in vitro and clinical | -Review clinical studies/in vitro trials -Analyze effect of GTE on oral premalignant lesions, plus other cancers (breast, lung, colon, etc). -Monitor parameters: inflammation, apoptosis, proliferation | -GTE is an affordable, safe chemopreventive agent -Useful as a supplement in oral cancer prevention -Possible integration in screening programs/complementary treatments | [185] |
Pomegranate extract | Lythraceae/Magnoliopsida | Standardized pomegranate extract (POMx) | in vitro | -Oral cancer cells (Ca9- 22, OC-2, HSC-3) vs. normal HGF-1 -Measurement of mitochondrial membrane potential, mitochondrial superoxide -Western blot, PCR (antioxidant genes, mitochondrial DNA) -Apoptosis (Annexin V, subG1) | -POMx as a selective anticancer agent for OSCC -Mechanism: mitochondrial oxidative stress -Requires preclinical/clinical studies to validate use in treatments | [186] |
Phytochemical Compounds | Class of Compounds | Methodology/Cancer Types | The Importance of Results | References |
---|---|---|---|---|
Oroselol | Phenolic compound | -Colorimetric test that measures activity of mitochondria (MTT assay), (viability, doses 15–120 µM, 48–72 h) -Clonogenic test (colony formation) -Transwell for migration/invasion -Western blot (LC3, p62, PI3K/AKT phosphorylation) -ANOVA p < 0.05 | -Demonstrates the potential of oroselol as an anticancer agent (oral carcinoma) -Highlights the role of autophagy and the PI3K/AKT pathway in oral carcinoma -Provides a mechanistic basis for novel chemoprevention strategies | [187] |
Anthocyanins | Flavonoid | -in vitro, animal studies, OSCC data. | -Anthocyanins are affordable, safe, and potentially chemopreventive -Supportive in decreasing the risk of OSCC, possibly adjunctive therapy -Extensive clinical studies are needed to confirm bioavailability and efficacy | [188] |
Resveratrol | Stilbene | 1. -In vitro (Ca9-22) and in vivo (nude mice) models siRNA for E-FABP, SREBP1 -qRT-PCR, RNAscopes, luciferase -Autophagy inhibitors, viability assays 2. -Mucosal fibroblasts exposed to arecolin ± resveratrol -Measurement of α-SMA, collagen I, ZEB1, miR-200a -Cell migration assays, contractility -Statistical analysis p < 0.05 3. -YD-10B cells, treated with resveratrol at various concentrations. -MTT (viability), immunoblot (TWIST, SLUG, E-cadherin); -Invasion assay (Boyden, Matrigel) -Statistical analysis p < 0.01 4. -Systematic review (PRISMA guidelines) + meta-analysis -Five studies were included in the statistical analysis -Assessment of neoplastic parameters: proliferation, apoptosis, overall effect size (ES) -Subgroups analyzed (cell type, exposure) | 1. -Points to SREBP1 as a new therapeutic target—Resveratrol as a selective inhibitor of tumor lipid metabolism. Possible adjuvant treatment for oral cancer 2. -Possible adjuvant therapy for OSF (precancerous)Prevents progression to oral carcinoma -Clear molecular mechanism: miR-200a 3. -Demonstrates the potential of resveratrol to block EMT in oral cancer -Can be used as a complementary natural therapeutic agent, possibly with existing chemotherapeutic 4. -May be an effective complementary agent in oral cancer prevention/treatment -Needs larger clinical trials for confirmation. -Supports integration of resveratrol into multifactorial therapeutic approaches | [189,190,191,192] |
Ubiquinones and β-carotene | Quinone/Carotenoide | -194 oral cancer patients, separated according to TNM stages -Measurement of vit. Antioxidants (CoQ10, β-carotene), antioxidant enzymes, Metabolic parameters (lipids, glycemia), inflammation markers (CRP, IL-6) -Statistical analysis (correlations p < 0.05) | -Suggests antioxidant supplementation in patients with OSCC -Highlights the link between metabolic disorders and cancer progression -Supports personalized nutritional interventions | [193] |
Yohimbine | Alkaloid | -MTT assay (IC50~44 µM) -Morphological observations (shrinkage, blebbing) -Measurement of ROS, mitochondrial potential (flow cytometry) -Concentrations 40–50 µM yohimbine | -Shows potential of yohimbine against oral-resistant cancer -Example of drug repurposing -Requires in vivo studies for validation | [194] |
Prenylflavones | Flavonoid | -Compound isolation/purification (chromatography, NMR, ESI-HRMS) -MTT tests on OSCC lines (SAS, T.Tn) + normal HaCaT cells -Molecular docking + dynamic simulations -Clonogenic assay -Flow cytometry (cycle block, apoptosis) -Wound healing assay (migration | -Demonstrates the potential of prenylflavones studied as anticancer agents with high selectivity for OSCC. -Anti-proliferative, anti-metastatic, and pro-apoptotic efficacy -Leads to the development of targeted prenylflavone-based therapies from Artocarpus altilis | [195] |
Piperlongumine (PL) | Alkaloid amide | -In vitro, MC-3, HSC-4 lines -Viability assays, Western blot (p38, JNK, ERK) -Autophagy blocked with hydroxychloroquine (HCQ) -Assessment of apoptosis, cytotoxicity | -PL has significant anticancer potential in oral cancer -Causes apoptosis and cytoprotective autophagy -Combination with autophagy inhibitors may improve therapeutic efficacy | [196] |
Semilicoisoflavone B (SFB) | Isoflavonoid | -MTT assay, flow cytometry (G2/M phase, Annexin V) -Western blot apoptosis proteins (Bax, Bcl-2, caspases) -NAC to block ROS -MAPK, Ras, Raf, MEK (phosphorylation) assessment | -SFB is a robust anticancer agent for OSCC -Complex mechanism: ROS, cycle blockade, MAPK Signaling -May be used clinically for OSCC management, requires further studies | [197] |
Cannabinoids | Terpenophenolic compounds | -Review of epidemiological data + in vitro studies on oral cancer cells -Analysis of cannabinoid regulated signaling pathways | -Can be used as adjuvant therapy with anticancer benefits + reduced side effects -Studies still needed to clarify risks vs. protection -Could improve the quality of life for oral cancer patients | [198] |
Vitexin | Flavone | -p53 inhibitor (PFT-α) for p53- dependent confirmation -PCR/Western blot p53, p21, Bax -MAPK inhibitor (PD98059) -MMP-2, PAI-1 analysis -viability, metastasis test | -Highlights the p53-dependent pathway in vitexin action -Demonstrates anti-cancer and anti-metastatic potential of vitexin in OSCC -Vitexin could be a promising therapeutic agent, requiring further studies | [199] |
Demethoxymurrapanine (DEMU) | Alkaloid | -Ca9-22 lines, CAL 27 (oral cancer), vs. normal cells (S-G) -Treatment 0–4 μg/mL DEMU, 48 h -Measurement of ROS, superoxide, glutathione -Evaluation of subG1, Annexin V, caspases 3/8/9 -DNA damage (γH2AX, 8-OH-dG) -NAC pt. testing the role of oxidative stress | -DEMU acts preferentially on OSCC cells, having anticancer selectivity -Potential therapeutic agent with minimal adverse effects -Further studies needed for clinical applicability | [200] |
Dehydroandrographolide (DA) | Diterpenoid lactone | -SCC9 lines -Wound closure, Boyden chamber (migration/invasion) -Gelatin zymography + Western blot MMP-2 -PCR MMP-2, TIMP-2, NF-κB, AP-1, SP-1 -In vivo xenograft model for metastases | -DA has important anti-metastatic potential in oral cancer -May be used to prevent tumor spread -Offers an alternative/complement to classical therapies, requires clinical trials | [201] |
Transferulic acid | Phenolic acid | -MTT assay (20–120 μg/mL, 24–48 h) -DAPI staining (nuclear morphology) -qRT-PCR (Bax, Mcl-1) -FACS/PI for cell death | -Demonstrates major anticancer potential by activating apoptosis in OSCC -Can be used alone or in combination with other treatments -In vivo studies needed for other cancers | [202] |
Fisetin | Flavonoid | -Flow cytometry (ROS, Ca2+, caspases) -DAPI staining (chromatin condensation) -Comet assay (DNA lesions) -Western blot apoptotic proteins -Confocal microscopy (cytochrome c, AIF, ENDO G) | -Fisetin is a potential anticancer agent in OSCC -Multiple mechanisms => receptivity to combination therapies -Basis for the development of novel treatments | [203] |
Carnosic acid (CA) | Diterpenoid | -In vitro: CAL27, SCC9 (proliferation, migrationROS, Ca2+, MMP assays) -In vivo: BALB/c nude mice, xenotransplantation (CAL27/SCC9) -Western blot apoptotic proteins, tumor histology | -CA has remarkable therapeutic potential as it is safe and effective -Can be combined with other treatments -Helps in understanding mitochondrial mechanisms | [204] |
Z-Ligustilide | Phthalide compound | -TW2.6 cells (hypoxic oral cancer) -Treatments with ligustilid + c-Myc/IRE1α inhibitors -Morphology, viability, migration analysis -γ- H2AX for DNA Damage -Combinatorial studies with radiation | -Potential therapeutic agent in oral cancer, including under hypoxia -May act as a sensitizer to radiotherapy -Requires future studies for combination therapies (ligustilide + radiation) | [205] |
α-Mangostin | Xanthone | -Treatment with α-mangostin on OSCC cells -Apoptosis assessment (nuclear fragmentation, annexin V/PI) -Mitochondrial membrane potential analysis -Cellular cycle study (CDK/cyclin) | -α-Mangostin could be an effective therapeutic agent with low toxicity -Acts via mitochondrial mechanism and G1 cycle arrest -Proposed as a complementary therapy in oral cancer | [206] |
Blumeatin | Flavonoid | -MTT assay (0–200 μM) on SCC-4 and hTRET-OME -Transwell (migration, invasion), wound healing-TEM for autophagy -Flow cytometry (ROS, MMP) -Western blot (LC3B, p62, Beclin 1) | -Blumeatin is a potent anticancer agent against OSCC -Also shows anti-metastatic effect (inhibits migration/invasion) -Higher selectivity against normal cells | [207] |
Kaempferol | Flavonoid | -Migration/invasion assays (SCC4 cells) -Analysis of mRNA/proteins MMP-2, TIMP-2 -MMP-2 transcription study, c-Jun activity -ERK1/2 phosphorylation measurement | -Kaempferol has metastasis prevention/treatment potential for OSCC -Molecular approach: blocking c-Jun, ERK1/2 -Possible to integrate into complementary clinical applications | [208] |
Quercetin | Flavonoid | 1. -Flow cytometry (Annexin V/PI, ROS, Ca2+) -Western blot apoptotic proteins (Bcl-2, Bcl-XL, Fas, casp-8 etc.) -Confocal microscopy for cytochrome c -Treatment interval 6–48 h 2. -KON cancer lines vs. MRC-5 normal fibroblasts -MTT test(cytotoxicity, 1.5625–200 µg/mL), 24–96 h -Morphological analysis (nuclear condensation) -Colony formation test -Migration/invasion test (Transwell) -ANOVA + Tukey post-test | 1. -Quercetin can be a promising therapeutic agent for oral cancer -Induces apoptosis via multiple pathways (ER + mitochondria) -Opens the way for future formulations/therapies in OSCC management 2. -Quercetin may be an adjuvant in standard OSCC therapy -Showing selectivity, lower adverse effects -Requires thorough mechanistic studies and in vivo confirmation | [209,210] |
Sulforaphane | Isothiocyanate | -SCC-9, SCC-14 cells, treated with 0–10 μM sulforaphane (24–48 h) -MTT (viability), wound healing, Boyden (migration/invasion) -Western blot (cathepsin S, LC3, phosphorylated ERK1/2) -Confocal microscopy (GFP-LC3 spots) | -Sulforaphane may be a potential oral anticancer therapeutic agent -Regulation of cathepsin S and autophagy is a new target -Substance derived from cruciferous vegetables, supporting the idea of dietary role in oral cancer prevention/treatment | [211] |
Anethole | Phenylpropene | -Malignant gingival cells (Ca9-22) -MTT, LDH assays for viability/proliferation -Apoptosis, autophagy, and ROS measured by flow cytometry -Western blot (p53, p21, caspase, NF-κB, etc.) -migration/healing assay | -Potential selective anticancer therapeutic agent, minimal impact on normal cells -May limit metastasis by blocking EMT -Useful as an adjuvant/complementary in existing cancer therapies | [212] |
Destruxin B | Cyclic peptide | -Inhibits viability of GNM lines, TSCCa (oral cancer) vs. normal gingival fibroblasts -MTT test (viability) at 24–72 h -Annexin V/PI, caspase-3 immunofluorescence -Western blot (Bax, Bcl-2, caspase-3) | -Destruxin B proves selective for oral cancer cells -Promising safety profile -Possible complementary agent in oral cancer therapies (e.g., metastatic forms) | [213] |
Cathepsin S (CTSS) | Protease enzyme | -OSCC lines, MP treatment -Cell viability, cell cycle (G2/M) -Western blot (caspase, PARP) -Autophagy study (LC3, beclin-1) -CTSS + p38/JNK role analysis | -Demonstrates a complex mechanism (apoptosis + autophagy -CTSS becomes a potential target for combination with MP -Offering new therapeutic strategies in OSCC, increasing tumor sensitivity | [214] |
Tetrandrine | Bisbenzylisoquinoline alkaloid | -MTT assay (viability) -DAPI, Annexin V/PI (apoptosis -Western blot (caspase, PARP, LC3, Atg-5) -Autophagy inhibitor studies (bafilomycin A1, 3-MA, chloroquine, NAC) | -A dual mechanism (apoptosis + autophagy) for tetrandrine is evidenced -Potential multifunctional anticancer agent, synergy with autophagy inhibitors of interest -Opens the way to further clinical applications in OSCC | [136] |
Lycopene | Carotenoid | -Lycopene/beta-carotene- treated KB-1 cells -Measurement of proliferation, connexin 43 expression (PCR, Western blot) -Gap-junction assay (scrape-loading, electron microscopy) -Carotenoid uptake analysis | -Lycopene has greater anticarcinogenic potential than beta-carotene in OSCC -Enhances intercellular communication (connexin 43), decreasing carcinogenesis -Supports the role of nutrition (tomato, carotenoids) in preventing oral cancers | [215] |
Pinosylvin | Stilbene | -SAS, SCC-9, HSC-3 lines treated with 0–80 μM pinosylvin -Western blot (MMP-2, TIMP-2, ERK1/2) -Gelatin zymography for MMP-2 activity -Wound healing + Transwell (migration/invasion) | -Pinosylvin has anticancer potential, preventing OSCC metastasis -Contributes to the development of therapies targeting MMP-2 and ERK1/2 -Could be an adjuvant agent in the prevention of metastasis | [216] |
Caffeic acid phenethyl ester (CAPE) | Phenolic acid | -Cell viability: trypan blue, live/dead assay -Soft agar assay for neoplastic transformation -Western blot (caspase-3, PARP, Bax, Puma) -DAPI staining for nuclear fragmentation | -CAPE as a promising agent in oral cancer treatment -Clarifies the role of Bax/Puma in apoptosis -Can be used in complementary therapies with reduced side effects | [217,218] |
β-Sitosterol | Phytosterol | -Cytotoxicity, MTT assay (KB cells) -Flow cytometry for apoptosis confirmation -mRNA analysis (caspase-3, caspase-9, BAX, BCL-2) -Bioinformatics (STITCH, docking) for compound–protein interactions | -Natural oral cancer therapeutic agent, potentially safer -May reduce side effects of conventional therapies | [217] |
Santamarine | Sesquiterpene lactone | -OC-2, HSC-3 cells (cancerous) vs. S-G (normal) -Measurement of ROS, mitochondrial superoxide, and GSH -Apoptosis (cytometry, Western blot, caspase) -DNA analysis (γH2AX, 8-hydroxy-2-deoxyguanosine (8-OH-dG)) -NAC effect (antioxidant) | -Substance with selective oral anticancer potential -Oxidative stress-type mechanism -> cell death -Basis for preclinical studies, capitalizing on the natural source, Michelia compressa | [219] |
Burmannic acid (BURA) | Terpenoid acid | -Viability testing (MTT) -Flow cytometry (cell cycle, apoptosis) -Mitochondrial superoxide measurement, membrane potential -Western blot for caspases -DNA damage (γH2AX, 8-OH-dG -NAC used to demonstrate oxidative stress involvement | -BURA has selective anticancer potential, decreasing overall toxicity -Oxidative stress is becoming a targeted strategy in the development of new natural anticancer drugs -Requires preclinical/clinical studies to validate the effect | [220] |
Silymarin | Flavonolignan | -In vitro assays on HSC-4, YD15, Ca9.22 lines (viability, Western blot, apoptosis) -In vivo studies (animal models) for tumor assessment and toxicity monitoring -Death receptor assays (DR5), caspase cascade | -Silymarin proves to be a promising oral anticancer agent, minimally toxic -Has the potential to be combined with other therapies, decreasing overall toxicity -Supports the use of natural phytotherapeutic compounds in oral oncology | [106] |
Phytochemical Compounds Formulation/Combination | Class of Compounds | Methodology/Cancer Types | Mechanism of Action | The Importance of Results | References |
---|---|---|---|---|---|
Silymarin in nanostructured lipid carrier (NLC) | Flavonoid complex | -Statistics Box-Behnken design 33 for optimization NLC -Characterization of PS, PDI, %EE -In-situ gel tested for SME release -Test on KB cells: IC50, apoptosis (Sub-G0) -Comparison of free SME vs. SME- NLCs vs. in-situ gel | -Generates ROS, favoring apoptosis -Inhibits KB cancer cells (low IC50 value) -Increased penetration and sustained release to the mucosa | -SME-NLCs-Plx/CP-ISG mucoadhesive system offers an effective strategy for localized treatment of oral cancer -Improves bioavailability and reduces the required dose -Alternative/addition to chemo/radiotherapy | [109] |
Polydatin (nanoencapsulation) | Stilbene derivative | -Syrian hamsters, DMBA induction for oral carcinogenesis -POL-PLGA-NPs administration -Tumor incidence, tumor volume measurement -Biochemical analysis (TBARS, LOOH, antioxidant enzymes) -Histopathology oral cavity -ANOVA, DMRT test | -Increases antioxidant enzymes (CAT, GPx, SOD) and non-enzymatic antioxidants (Vit. C, E, GSH) -Decreases Phase I enzymes (Cit P450, Cit b5) and increases Phase II (GST, GGT, GR) -Reduces lipid peroxidation and oxidative damage -Supports Nrf2, AMPK, and cell homeostasis | -Demonstrates the role of polydatin (nanoencapsulated) as an oral chemopreventive agent -Nanotechnology improves bioavailability and efficacy -Promising strategy for oral anticancer therapies with low toxicity | [221] |
α-Mangostin (α-MG) (mucoadhesive film) | Xanthone | -α-MG mucoadhesive film formulation -MTT test on SCC25 (IC50~152.5 µg/mL) -HPV-16 pseudovirus test (attachment vs. post- attachment stage) -NO reduction test (RAW264.7 cells) -Fibroblast migration test (in vitro healing) | -Cytotoxic effect on SCC25 at conc. > 125 µg/mL -Inhibits the attachment of pseudovirus HPV-16 (not further steps) -Reduces NO production in macrophages (anti-inflammatory effect) -Promotes fibroblast migration, thus improving healing | -Potential agent for oral cancer, topical administration -May prevent HPV infection (oral cancer risk factor) -Anti-inflammatory and pro-healing effects -Possible clinical use in the management of oral cancer and associated lesions | [222] |
Nanoformulated rosemary extract | Plant extract | -Obtaining chitosan NP with rosemary extract -Hep-2 lines (OSCC) -Cytotoxicity (MTT) -Cell cycle analysis, apoptosis -ROS measurement -Autophagy observation (TEM microscopy) | -Dose-dependent cytotoxic effect -Cycle arrest in G2/M phase -Increased ROS, cell death -Observation of autophagosomes (autophagy) -Chitosan encapsulation increases stability/bioactive extract | -Non-invasive method with potential to reduce the toxicity of standard therapy -Increases the efficacy of nanoparticle rosemary -Can be integrated in combination treatments for OSCC | [223] |
Nanoemulsion-based orodispersible film of Guava | Plant extract formulation | -Nanoemulsion GLO:VCO, characterization (size, zeta potential) -Film formulation (1–30% nanoemulsion) alginate based -Testing of anticancer activity: IC50, colony formation, invasion, apoptosis (Annexin V) -Stability at 25 °C for 1 year | -Formation of GLO:VCO nanoemulsion (70:30) with droplets ~50 nm -Incorporation in orodispersible film (alginate) -Anticancer effect: inhibition of colony formation, migration, induction of apoptosis (Annexin V) -Stability 1 year, maintaining activity | -Non-invasive oral treatment, targeted directly at the tumor -Orodispersible film with nanoemulsion: easy administration while maintaining anticancer activity -Opens the way for new local anticancer pharmaceuticals with potential for clinical integration | [224] |
Quercetin Formulation | Flavonoid | -Review of studies on quercetin in oral diseases -Discussion on nano/micro formulations, controlled systems -Integration of quercetin in topical products, gels, capsules, etc. | -Antioxidant, protection against oxidative stress -Antibacterial, anti-inflammatory (reduces gingival inflammation, etc.) -Oral anticancer (inhibits proliferation, induces apoptosis) -Innovative delivery systems (nanoparticles, controlled release) increase stability/absorption | -Great potential in the treatment of oral conditions, including OSCC -Modern formulations may improve stability and local penetration -Prospects for clinical and industrial research for dental/medical products | [44] |
Thymoquinone (TQ) + Cisplatin | Quinone + Chemotherapy agent | -UMSCC-14C lines (oral cancer) vs. OEC (normal cells) -Cytotoxicity assays, short/long (6h+) -Expression assays p53, Bcl-2, caspase-9 -Apoptosis % compared to TQ, CDDP, combination | -CDDP: cytotoxic for both tumor and normal cells -TQ: selective cytotoxic, induces apoptosis via p53↑, Bcl-2↓, caspase-9↑ -TQ + CDDP combination: additive/synergistic effect, partially protects normal cells | -Thymoquinone can be an adjuvant for cisplatin, reducing the required dose -Increases treatment specificity, decreasing systemic toxicity -Opens prospects for the use of TQ in combination regimens in oral cancer | [225] |
Anethole + Cisplatin | Phenylpropene + Chemotherapy agent | -Ca9-22 cells (oral cancer) -MTT, LDH, Hoechst assay (viability, cytotoxicity) -Wound healing, colony formation -Apoptosis assays (ΔΨm, caspases) -Western blot for MAPK, β-catenin, NF-κB | -Combination anethole + cisplatin: -Increase oxidative stress, apoptosis -Inhibits cell migration and growth, decreases colony formation -Blocks MAPK, β-catenin, NF-κB -Clear synergy, reducing cisplatin resistance | -Combination of anethole + cisplatin as a more effective and less toxic therapy -Future clinical applications supported by synergistic studies -Approach targeting multiple pro-tumor pathways | [226] |
Apigenin + Oxaliplatin (OXA) | Flavonoid + Chemotherapy agent | -HSC-3 cells, groups: control, apigenin, OXA, combination -Wound healing, invasion assay, 3D culture (angiogenesis) -qPCR for LINC00857 -Proliferation, apoptosis analysis | -Low doses of OXA induce EMT (migration, invasion, angiogenesis) -Apigenin inhibits LINC00857 expression => blocks EMT -Combines the anticancer effect of apigenin with OXA, inhibiting proliferation + metastasis of OSCC cells | -Apigenin + OXA strategy prevents OSCC metastasis -LINC00857 becomes a molecular target -Possible safer treatment, reduced OXA doses, decreasing side effects | [227] |
Quinic acid (QA)+Cisplatin | Hydroxycarboxylic acid + Chemotherapy agent | -MTT assay for cytotoxicity (QA and QA + cisplatin) -DAPI staining, RT-PCR (pro/anti-apoptotic gene expression) -Flow cytometry and Western blot for apoptosis validation, Akt signaling, cyclin D1 | -QA reduces expression of anti-apoptotic genes -Inhibits cyclin D1 and Akt pathway result decreases proliferation -Increases the anticancer effect of cisplatin, favoring apoptosis | -QA can be an oral anticancer agent, potentiating cisplatin -Offers therapeutic alternatives and potentially lower doses of cisplatin, with low toxicity -Opens the way for preclinical/clinical studies | [228] |
Resveratrol (RV) + Polydatin (PD) | Stilbene + Stilbene derivative | -In vitro studies on OSCC lines and in vivo (animal models) -Biodistribution, pharmaceutical (liposomes) evaluation -Synergy analysis with other chemotherapeutics -Observations on proliferation, metastasis, and apoptosis parameters | -RSV and PD demonstrate significant anticancer effect (in vitro/in vivo) -Liposomal formulations increase stability/efficacy -Synergistic effect with chemotherapeutics, reduces resistance -Low systemic toxicity | -Provides directions for the development of advanced delivery systems -Opens clinical perspectives for RSV/PD in OSCC -Potential to become a complementary therapy with minimal adverse effects | [229] |
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Mitea, G.; Schröder, V.; Iancu, I.M. Bioactive Plant-Derived Compounds as Novel Perspectives in Oral Cancer Alternative Therapy. Pharmaceuticals 2025, 18, 1098. https://doi.org/10.3390/ph18081098
Mitea G, Schröder V, Iancu IM. Bioactive Plant-Derived Compounds as Novel Perspectives in Oral Cancer Alternative Therapy. Pharmaceuticals. 2025; 18(8):1098. https://doi.org/10.3390/ph18081098
Chicago/Turabian StyleMitea, Gabriela, Verginica Schröder, and Irina Mihaela Iancu. 2025. "Bioactive Plant-Derived Compounds as Novel Perspectives in Oral Cancer Alternative Therapy" Pharmaceuticals 18, no. 8: 1098. https://doi.org/10.3390/ph18081098
APA StyleMitea, G., Schröder, V., & Iancu, I. M. (2025). Bioactive Plant-Derived Compounds as Novel Perspectives in Oral Cancer Alternative Therapy. Pharmaceuticals, 18(8), 1098. https://doi.org/10.3390/ph18081098