Introduction
Cisplatin – General description
Mechanisms of cisplatin resistance in cancer cells
Mechanism of resistance | Effect | Involved molecular mechanism |
---|---|---|
An increase in DNA repair machinery activity directly protects genomic DNA from cisplatin effects. | Increased activity of: nucleotide excision repair (NER), homologous recombination (HR), nonhomologous end joining (NHEJ), Fanconi anaemia pathway translesion synthesis (TLS). Mismatch repair (MMR) deficiency. | |
Changes is epigenetics and transcription profile [10] | Altered expression of cisplatin resistance phenotype proteins: involved in cisplatin trafficking (CTR1, TMEM205, ATP7A and ATP7B), transcription regulators (f.i. histone H1 and H3, SIRT1, GCF2, Nrf2, Snail, TWIST), small GTPases (Rab5, Rac1, RhoA, Rab8), cytoskeletal proteins, endocytosis/exocytosis regulators (ERC, STX6), chaperones (HSP 10, 27, 60 70, 90), ribosomal proteins and others. | Overexpression of chromatin remodeling enzymes as Tip60 acetyl-transferase or histone deacetylases 1, 3 and 4. The activity of histone demethylase as RBP2/KDM5A/Jarid1A - required for cisplatin-tolerance phenotype. Hypermethylation of promoter regions - reduced gene transcription and contributing drug resistance. Among others p53, p73 and insulin-like growth factor-binding protein-3 promoters’ hypermethylation were strongly correlated with cisplatin resistance. |
Cisplatin chemical deactivation and ROS scavenging. | Glutathione sulfhydryl groups are highly reactive toward cisplatin thus sequestering it and limiting its accessibility. Glutathione and proteins like thioredoxin and peroxiredoxin limit oxidative stress caused by cisplatin. Carbonyl reductase (CBR1), aldo-keto reductases - AKR1C1 and AKR1C3 activity was implied in resistance-phenotype development. | |
The decreased fraction of cisplatin able to interact with its molecular targets. | CTR1 downregulation limits cisplatin efflux and generates cisplatin-resistant phenotype. Increased expression of cell membrane (ATP7B and MRP 1–5) or vesicular (ATP5A) transporters augments active cytoplasmic efflux of cisplatin in resistant cells. Increased cisplatin accumulation in cellular compartments as Golgi, lysosomes, melanosomes and exosomes has recently gained attention as a potential mediator of cisplatin resistance. |
L.p | Compound | Pharmacological/biological activity | Type of study | CPT chemosensitization - mechanism of action | References |
---|---|---|---|---|---|
Classical autophagy inhibitors | |||||
1. | Chloroquine and its derivatives (CQ) | - multi-active quinoline derivative - anti-inflammatory, anti-viral and anti-parasitic activity - autophagosome-lysosome fusion inhibitor - accumulates in lysosomes - triggers LMP | In vitro: NSCLC, oesophageal cancer, ovarian cancer, melanoma, urothelial carcinoma, gastric cancer, salivary gland carcinoma, endometrial cancer and tongue squamous carcinoma In vitro: glioblastoma, pediatric medulloblastoma cell lines and atypical teratoid/rhabdoid tumor In vivo: mouse xenograft CPT-resistant oesophageal, melanoma and hepatocarcinoma cancer model | - ↑ CPT induced apoptosis and/or senescence - loss mitochondrial membrane potential - ↑ caspases 8,3 level - selectivity in some experiments - no effect in normal cell lines - ↑ autophagy - ↓ late stage autophagy flux - ↑ROS - no influence - ↓ tumor mass | |
2. | Bafilomycin-A1(Baf-A1) | - a selective inhibitor of V-ATPase ATP6V0C/V0 subunit c - SERCA Ca2+ pump inhibitor - inhibits -autophagosome-lysosome fusion and/or lysosomal digestion | In vitro: bladder, oesophageal and cervical cancer, tongue squamous cell carcinoma | - ↓ of lysosomal CPT uptake thus ↑ the DNA-bound CPT portion - ↑ lysosomal biogenesis by c-Abl/TFEB pathway | |
3. | 3-Methyladenine (3-MA) | - non-specific phosphosphatidylinositol 3-kinases (PI3K) inhibitor | In vitro: cervical cancer, gliomas, salivary adenoid cystic carcinoma, osteosarcoma, ovarian cancer, NSCLC, nasopharyngeal carcinoma, laryngeal cancer, hepatocarcinoma and urothelial carcinoma In vitro: tongue squamous cell carcinoma In vivo: Human Salivary Adenoid Cystic Carcinomaxenograft models | - ↑ caspase-dependent apoptosis - mitochondria hyperpolarisation - ↑ ER-stress markers which were linked to caspase-4 and caspase-3 activation - no effect - ↓ tumor mass | |
4. | Wortmanin (WT) | - non-specificphosphosphatidylinositol 3-kinases (PI3Ks) inhibitor | In vitro: cholangiocarcinoma, NSCLC In vivo: cholangiocarcinoma xenograft model | - ↑ intrinsic apoptotic pathway - acts selectively towards rapidly proliferating cells - ↓ tumor mass | |
Compounds well specified molecular targets | |||||
5. | mTOR/PI3K inhibitors: PKI402 AZD2014 | - mTOR is a regulator of cellular metabolism linking nutrient status and growth factor (GF) signaling with autophagy induction | In vitro: hepatocarcinoma In vitro: glioblastoma, NSCLC, normal cells | - ↑ lysosomal biogenesis (mtROS/TFEB) - ↑ lysosomes number - induced mitochondrial depolarization, - ↑mtROS generation - ↑apoptosis - ↓ cell death | |
6. | MAPK inhibitors (UO126) | - MAPKs are kinases responsible for extra and intracellular signal transduction, amplification and coordination | In vitro: NSCLC In vitro: oesophageal cancer | - upregulation of thymidylate synthase and thymidine phosphorylase that grants CPT resistance - ↓ autophagy - ↑ apoptosis - ↑ senescence - ↓cellular growth - ↓apoptosis - ↓senescence | |
7. | MPT0L145 | - selective FGF-R inhibitor | In vitro: bladder cancer | - ↓ viability of in CPT-treated CPT-resistant bladder cancer (mitochondrial dysfunction, ROS production, and DNA damage) - ↑ incomplete autophagic flux | [74] |
8. | Nimotuzumab | - anti-EGF-R monoclonal antibody commonly utilized in cancer therapy | In vitro: oesophageal squamous cell carcinoma | - ↑ sensitivity towards CPT or paclitaxel-induced viability reduction - ↑ autophagy | [75] |
9. | PIK3C3/Vps34 inhibitor: SAR405 | - PIK3C3/Vps34 is a lipid kinase implicated in vesicular trafficking and autophagosome maturation | In vitro: urothelial carcinoma | - ↓ cell viability | |
10. | Cepharanthine | - cholesterol trafficking inhibitor targeting Niemann-Pick disease type C1 (NPC1) protein - preventing cholesterol efflux into the cytoplasm - disruption of lysosomes | In vivo: breast and lung cancer xenograft models | - synergize with CPT to ↓ tumor growth | [77] |
Compounds influencing cellular metabolism | |||||
11. | Metformin | - antidiabetic drug - mitochondrial complex I and mitochondrial glycerophosphate dehydrogenase inhibitor - glutaminase inhibitor - ↑β-oxidation, glucose uptake, glycolysis - antineoplastic activity | In vitro: breast and cervical cancer cells, | - ↓ in CPT induced autophagy - ↑apoptosis - ↓ cancer cells proliferation - ↓ of autophagy secondary to ↓ of ammonia production | |
12. | 2-deoxy-D-glucose (2-DG) | - glycolysis inhibitor | In vitro: colon cancer, neuroblastoma, glioma grade IV | Cellular-specific effects: - ↑ endoplasmic reticulum (ER) stress and autophagy - ↑ apoptosis | |
13. | Insulin | - a peptide hormone secreted by the pancreas implicated in glucose cellular uptake and metabolism regulation | In vitro: oesophageal squamous cell carcinoma | - ↑ Akt and mTOR expression and ↓ autophagy initiation which correlated with ↑ the apoptotic ratio | [82] |
14. | Nicotinamide Phosphoribosyltransferase inhibitor: FK866 | - inhibits enzyme the catalyzing conversion of nicotinamide to nicotinamide mononucleotide | In vitro: neuroblastoma and cervical cancer | - ↑ cell death | [83] |
Natural compounds and their derivatives | |||||
15. | Oridonin | - bioactive ent-kaurane diterpenoid, a major active constituent of Rabdosia rubescens, which has been widely used in traditional Chinese medicine (anti-cancer, anti-inflammatory) | In vitro: ovarian cancer, NSCLC | - ↑apoptosis - ↓ Belin-1 level - ↓ autophagy - limits adverse effects of therapy (CPT-induced nephrotoxicity in vivo in mice) | |
16. | Phenoxofiol (PXD) | - an isoflavone analog with widely proved anticancer activity - inhibitor of apoptosis protein (XIAP) and FLICE inhibitory protein (FLIP) - direct inhibition of topoisomerase II and ENOX2 (ecto-NOX disulfide-thiol exchanger 2) | In vitro: ovarian cancer | - XIAP downregulation - ↓ autophagy - ↓ Beclin-1 level - limits adverse effects of therapy (CPT-induced neurotoxicity in vitro) | |
17. | Andrographolide | - naturally occurring labdane diterpenoid - anti-inflammatory, antiviral, antioxidant and anticancer action - may disrupt autophagosome-lysosome fusion - activator of Nrf2 | In vitro: NSCLC and colon cancer In vivo: NSCLC xenograft model | - ↑ apoptosis - ↓ PTEN - ↑ lifespan | |
18. | 4-Acetylantroquinonol | - tetrahydro ubiquinone derivative found in Antrodia camphorate, mushroom popular in Taiwan and Chinese medicine - anti-cancer activity | In vitro: ovarian cancer cell lines In vivo: ovarian cancer xenograft models | - ↑ apoptosis - ↓ autophagy - ↓ Akt and mTOR activity - ↓ tumor growth | [46] |
19. | Pristimerin | - quinonemethide triterpenoid with anti-cancer activity isolated from Celastraceae and Hippocrateaceae - proteasome and telomerase inhibitor - ↓ MEK/ERK, EGF-R, PI3K/Akt, Wnt/β-catenin, NfxB - ↑ JNK - ↓ autophagy/↑ autophagosome accumulation | In vitro: NSCLC In vivo: NSCLC mice xenograft model | - ↓ miR-23a - ↓ Akt and GSK3B phosphorylation - ↓ autophagy - ↓tumor growth | |
20. | Icariin | - flavonoid usually derived from Epimedium sagittatum - anti-cancer, anti-inflammatory, anti-oxiant, anti-apoptotic | In vitro: multidrug-resistant ovarian cancer cell | - ↑ apoptosis - ↓ autophagic flux | [93] |
21. | Melatonin | - human hormone regulating the sleep-wake cycle - antioxidant - Nrf2 activator - ↑/↓ autophagy (may be cell line specific) | In vitro: cervical cancer and head and neck squamous cell carcinoma | - ↑ apoptosis - ↓ mitophagy (secondary to ↓ JNK/parkinin activity) - ↑ mitochondrial ROS | |
22. | Procyanidins (OCP) | - Flavonoids - anti-oxidative, anti-inflammatory, antimicrobial, antiviral and anti-cancer activity | In vitro: laryngeal carcinoma | - ↑ apoptosis - ↑ autophagy | [97] |
23. | Neferine | - bisbenzylisoquinoline alkaloid with anti-cancer activity derived from Lotus seeds - P-glycoprotein 1 inhibitor | In vitro: NSCLC | - ↑ ROS generation - ↓ PI3K/Akt/mTOR pathway - ↑ autophagy (↑LC3B-II/LC3B-I ratio) - ↓ Beclin-1 and PI3KCIII | |
24. | Hyperoside | - flavonol glycoside present mainly in members of Hypericum and Crataegus genera - anti-inflammatory, anti-oxidant and anticancer activities | In vitro: ovarian cancer | - ↑ apoptosis - ↑ autophagy - selective towards CPT-resistant cells characterized with PGRMC1 expression and autophagic flux | [100] |
25. | Bu-Zhong-Yi-Qi Decoction (BZYQD) | - Chinese herbal medication comprising extracts from six different herbs - anti-cancer activity | In vitro: NSCLC | - ↑ apoptosis - ↑ autophagy (accumulation of LC3-II and Atg7) - ↑ ROS generation | [101] |
26. | Monanchocidin A (MonA) | - an alkaloid isolated from marine sponge Monanchora pulchra - cytotoxic properties in cancer cell lines | In vitro: resistant germ cell tumor cell line, prostate and bladder cancer | - selectivity (cancer specific) - ↑ cell death - ↑ unselective autophagic protein degradation - ↑ LMP at higher concentrations | [102] |
27. | (−)-Epigallocatechin gallate (EGCG) | - polyphenolic catechin - anti-cancer activity in vitro | In vitro: colorectal cancer | - ↓ cancer cells proliferation - ↑ cell death - ↑ autophagosome formation and accumulation | [103] |
28. | Chalcone-24 (Chal-24) | - a member of chalconoids - anti-microbial, anti-inflammatory and anti-neoplastic activity | In vitro: NSCLC | - ↑ apoptosis - ↑ JNK/Bcl-2/Beclin 1 dependent autophagy induction | [104] |
29. | Resveratrol | - polyphenolic compound - anti-oxidant, anti-inflammatory, cytoprotective, anti-neoplastic effect - pleiotropic biological activity | In vitro: NSCLC | - ↑ autophagic flux - ↑ apoptosis (↑Bax expression and ↓Bcl-2 and Akt phosphorylation) | |
30. | Gambogic Acid (GA) | - a xanthonoid compound derived from Garcinia hanburyi - anti-cancer activity proved in vitro and in vivo | In vitro: NSCLC | - ↑ cancer growth inhibition - ↑ autophagy - ↓ Akt/mTOR pathway | [108] |
31. | GMI -an immunomodulatory protein derived from Ganoderma microsporum fungus | - antineoplastic activity was proved in vivo after oral administration - ↑ ER stress/calcium/Akt/mTOR pathway and triggers autophagic cell death attributed to unfused autophagosome accumulation | In vitro: NSCLC | - ↑ apoptosis - downregulation of ERCC1, XPF, and survivin | [109] |
32. | Glaucocalyxin B (GLB) | - diterpenoid with anti-cancer activity extracted from Rabdosia japonica. | In vitro: gastric cancer | - DNA damage - ↑ ROS production - ↑ autophagy | [110] |
33. | Poly-unsaturated fatty acids (PUFAs): Arachidonic acid (AA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) | - multidirectional positive effects in human organism | In vitro: NSCLC, cervical cancer | - ↑ apoptosis (↑caspase 3/7 activity) - ↑ autophagy - ↓ cancer cells viability - ↓ caspase 3 and PARP cleavage, but with Bcl-2 downregulation and↓ LC3B-II expression - limiting CPT-mediated nephrotoxicity in mice | |
Other Compounds | |||||
34. | Quinacrine (QC) | - anti-malarial drug - structurally related to CQ | In vitro: ovarian cancer and head and neck squamous cell carcinoma | - ↑ autophagic flux - ↑ autophagosome accumulation | |
35. | Graphene oxide | - medical nanotechnology, (drug delivery systems) - may trigger LMO - subsequent ↑ autophagy induction and ↓ late-stage flux (↓ lysosomal degradation) | In vitro: cervical, prostate, ovarian and colon cancer In vitro: NSCLC | - ↑ cell death - ↑ necrosis - ↑ autophagy - no influence | |
36. | Proteasome inhibitor: bortezomib | - proteasomes are responsible for protein degradation - ↓ autophagic flux (↓ cathepsin activity secondary to sustained ERK activation) | In vitro: ovarian cancer | - ↑ cell death | [117] |
37. | Zoleandronic acid (ZA) | - treatment of multiple bone disorders as osteoporosis and bone metastasis | In vitro: salivary adenoid cystic carcinoma cell line | - ↑ apoptosis - ↑ ROS production - LC3B autophagy marker accumulation | [118] |
38. | Lithium (Li) | - multiple biological effects - ↑ autophagy induction - late-stage autophagy inhibition and vesicles accumulation | In vitro: oesophageal and colorectal cancer | - ↑ cell death - accumulation of cytoplasmic vesicles - LMP induction | [119] |
39. | C60(Nd) nanoparticles (C60(Nd)) | - medical nanotechnology, (drug delivery systems) | In vitro: cervical cancer | - ↑ cell death | [120] |