Alternative Options for Skin Cancer Therapy via Regulation of AKT and Related Signaling Pathways
Abstract
1. Introduction
2. AKT and Related Signaling Pathways Are Important in Skin Cancer Regulation
3. AKT and Related Signaling Pathway Inhibitors for Skin Cancer Regulation
3.1. Isorhamnetin
3.2. Curcumol
3.3. Polyphyllin I
3.4. Herbacetin
3.5. Luteolin
3.6. Sinomenine
3.7. Syringic Acid
3.8. Ginkgo Biloba Exocarp Extract
3.9. α-Mangostin
3.10. Silibinin (Silybin)
3.11. Curcumin
3.12. Other Bioactive Components
4. Perspectives
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Search Strategy and Selection Criteria
References
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Compounds | Plants | Cancer Types | Cell Lines | Mechanisms | Ref. |
---|---|---|---|---|---|
Isorhamnetin | Persicaria thunbergii H., Elaeagnus rhamnoides (L.) | melanoma | B16F10 | proliferation↓, migration↓ pAKT↓, PFKFB4↓ | [31] |
Curcumol | Curcuma wenyujin | melanoma | B16F10 | viability↓, colony formation↓ migration↓, pAKT↓, c-MET↓, miR-152-3p↓ | [33] |
Polyphyllin I | Paris polyphylla | melanoma | A375 | cells growth↓, migration↓, invasion↓, cell cycle progression↓, apoptosis↑, Bax↑, cleaved caspases-3↑, Bcl-2↓ autophagy↑, Beclin 1↑, LC3II ↑, p62 ↓ pPI3K↓, pAKT↓, pmTOR↓ | [36] |
Herbacetin | Flaxseed, ramose scouring rush herb | SCC, melanoma | JB6, A431, SK-MEL-5, SK-MEL-28 | AKT1/2 activity↓, ODC activity↓, growth↓, neoplastic transformation↓, pGSK3β↓, ODC activity↓, AP1 activity↓, NF-κB activity↓, pERK1/2↓, p65↓ | [38] |
melanoma | A375, Hs294T | tumor growth↓, angiogenesis↓, pEGFR↓, pAKT↓, pERK ↓ pGSK3β↓, ODC activity↓, AP1 activity↓, NF-κB activity↓ | |||
Luteolin | Reseda luteola | melanoma | A375.S2 | proliferation↓, migration↓, invasion↓, apoptosis↑, MMP-2↓, MMP-9↓, TIMP-1↑, TIMP-2↑, pAKT1↓, pPI3K↓ | [41] |
Sinomenine | Sinomenium acutum | melanoma | B16F10 | cell viability↓, apoptosis↑, Bax↑, Bcl-2↓, caspase-3 activity↑, autophagy↑, Beclin-1↑, LC3II/LC3I ratio↑, pp62/SQSTM1↓, pAKT↓, pmTOR↓ | [45] |
Syringic acid | Euterpe oleracea, Rhus javanica | non-melanoma | HaCaT | UVB-induced COX-2↓, UVB-induced MMP-1↓, UVB-induced PGE2 generation↓, UVB-induced AP-1 activity↓, pERK1/2↓, pJNK1/2↓, pp38↓, pMEK1/2↓, p-MKK4/7↓, pMKK3/6↓, pB-Raf↓, pAKT↓, pSrc↓, EGFR↓, UVB-induced cyclooxygenase-2↓, matrix metalloproteinase-1↓, prostaglandin E2↓ | [48] |
Ginkgo biloba Exocarp Extract | Ginkgo biloba L. | melanoma | B16F10 | proliferation↓, migration↓, heterogeneous adhesion↓, pPI3K↓, pAKT↓, NF-κB↓, MMP-9↓ | [51] |
Silibinin | Milk thistle plant (Silybum marianum) | BCC | ASZ001, Sant-1, GDC-0449 resistance ASZ001 | growth↓, colony formation ↓, pEGFR↓, pAKT↓, cyclin D1↓, Gli-1↓, SMO↓, SUFU↓, apoptosis↑, caspase-3↑, Bcl-2↓ | [56] |
Silybum marianum (L.) Gaertn., Asteraceae | BCC | ASZ, BSZ | cell growth↓, clonogenicity↓, apoptosis↑, pEGFR↓, pERK1/2↓, pAKT↓, pSTAT3↓ | [57] | |
Curcumin | rhizome of Curcuma longa | melanoma | A375 and C8161 | proliferation↓, invasion↓, G2/M phase cell-cycle arrest↑, autophagy↑, pAKT↓, pmTORC1↓, pp70S6K↓ | [60] |
Pristimerin | Celastraceae, Hippocrateacea | uveal melanoma | UM-1 | apoptosis↑, viability↓, colony formation↓, mitochondrial membrane potential↓, ROS level↑, G0/G1 phase arrest↑ migration↓, invasion↓ pAKT↓, pFoxO3a ↓, Bim↑, p27Kip1↑, cleaved caspase-3↑, PARP↑, Bax↑, Cyclin D1↓, Bcl-2↓ | [61] |
Gambogic acid | resin of Garciania hanburyi | melanoma | A375, B16F10, | proliferation↓, migration↓, invasion↓, adhesion↓, EMT↓, angiogenesis processes↓ MMP-2 and MMP-9 activities↓ PI3K–AKT–mTOR signaling pathway↓ | [62] |
Melittin/Bee Venom | honey bees (Apis mellifera) | melanoma | B16F10, A375SM, SK-MEL-28 | growth↓, colony-forming ability↓, migration↓, invasion↓, apoptosis↑, cleaved caspase-3 and -9↑, pPI3K↓, pAKT↓, mTOR↓, ERK↓, p38↓ | [63] |
Kaempferol | piper | melanoma | A375 | proliferation↓, migration↓, colony formation↓, apoptosis↑, G2/M cell cycle arrest↑, pmTOR↓, pPI3K↓, pAKT↓ | [64] |
Euplotin C | Euplotes crassus | melanoma | A375, 501Mel, MeWo, HDFa | viability↓, apoptosis↑, migration↓, B-Raf↓, pERK 1/2↓, pAKT↓ | [65] |
Lycorine | Lycoris radiate spider lilies (Lycoris), daffodils (Narcissus) and snowdrops (Galanthus) | malignant melanoma | HEMa, A375 | proliferation↓, cell migration↓, invasion↓, apoptosis↑, caspase-3↑, Bax↑, Bcl-2↓, pAKT↓, pmTOR↓, 4EBP1↓ | [66] |
Oxyfadichalcone C | Oxytropis falcate | melanoma | A375 | proliferation↓, G1 phase arrest↑, apoptosis↑, migration↓, invasion↓, p27↑, cyclin D1↓, ppRb↓, pIntegrin β1↓, MMP-2/9↓, metastasis↓, pPDK1↓, pAKT↓, pGSK-3β↓, pmTOR↓, pp70s6k↓, pERK↓ | [67] |
Isoliquiritigenin | Glycyrrhizae Radix | melanoma | A375 | proliferation↓, G2/M cell cycle arrest↑, mTOR↓, RICTOR↓, pAKT↓, pGSK-3β↓ | [68] |
Muniziqi granule/harmine | Peganum harmala, Cichorium intybus, Dracocephalum moldavica, Ocimum basilicum, Althaea rosea, and Nigella glandulifera | melanoma | B16F10 | proliferation↓, autophagy, autophagosome formation↑, LC3-II↑, P62↓, apoptosis↑, G1 cell cycle arrest↑, pAKT↓, pmTOR↓, pERK1/2↓ | [69] |
Apigenin | Various fruits and vegetables | A375, C8161 | proliferation↓, migration↓, invasion↓, apoptosis↑, G2/M cell cycle arrest↑, cleaved caspase-3↑, cleaved PARP↑, pERK1/2↓, pAKT↓, pmTOR↓ | [70] | |
Casticin | Fructus viticis | melanoma | B16F10 | migration↓, invasion↓, MMP-9↓, MMP-2↓, MMP-1↓, FAK↓, 14-3-3↓, GRB2↓, AKT↓, NF-κB↓, p65↓, SOS-1↓, p-EGFR↓, p-JNK 1/2↓, uPA↓, Rho A↓ | [71] |
Chrysin | passionflower, silver linden, honey, propolis | melanoma | A375.S2 | mobility↓, migration↓, invasion↓, MMP-2 activity↓, GRB2↓, SOS-1↓, PKC↓, pAKT (Thr308)↓, NF-κBp65↓, NF-κBp50↓ uPA↓, N-cadherin↓, MMP-1↓, MMP-2↓, VEGF↓, E-cadherin↑, NF-κBp65↓ | [72] |
Berberine | the roots and bark of Berberis genus | melanoma | A375.S2 | morphological changes↑, viability↓, mobility↓, migration↓, invasion↓, MMP-9 activity↓, MMP-1↓, MMP-13↓, E-cadherin↑, N-cadherin↓, RhoA↓, ROCK1↓, SOS-1↓, GRB2↓, Ras↓, pERK1/2↓, pc-Jun↓, p-FAK↓, pAKT↓, NF-κB↓, uPA↓, PKC↓, PI3K↓ | [73] |
caffeic acid n-butyl ester | skin carcinoma | A431 | Apoptosis↑, Bax↑, Bcl-2↓, ROS↑, MMP↓, G2 phase arrest↑, migration↓, pmTOR↓, pPI3K, pAKT↓ | [74] |
Compounds | Plants | Cancer Types | Model | Treatment | Mechanisms | Ref. |
---|---|---|---|---|---|---|
Isorhamnetin | Hippophae rhamnoides L. | melanoma | C57BL/6 mice injected with B16F10 cells, 1 × 105 | 20 mg/kg per day; for 7 days | Proliferation↓, Ki67↓ | [31] |
Curcumol | Curcuma wenyujin | melanoma | C57BL/6 mice injected (s.c. into the right lower paw and i.v. into the tail vein) with B16 cells, 2 × 106 | 20 mg/kg, i.p.; 3 times per week; for 30 days | proliferation↓, growth↓ invasion↓, metastasis↓ | [33] |
Polyphyllin I | Paris polyphylla | melanoma | male BALB/c -nude mice with A375 cells, 2 × 106 | Polyphyllin I 5 mg/kg; i.p.; once a day for 35 days | tumor weight↓, tumor size↓ apoptosis↑, TUNEL positive cells↑, Ki67↓ | [36] |
Herbacetin | Flaxseed, ramose scouring rush herb | SCC | -DMBA/TPA model; Hairless SKH:HR-1-hrBr (SKH-1) (8–9 weeks old), initiation with DMBA (200 nmol), and promotion with 17 nmol of TPA in acetone, topically applied twice weekly for 20 weeks -solar–UV induced-skin carcinogenesis model; exposed to solar–UV (48 kJ/UVA/2.9 kJ/UVB) three times weekly for 12 weeks -xenograft model; Athymic mice (Cr:NIH(S), NIH Swiss nude, 6–9-wk-old) with SK-MEL-5 cells, 3 × 106 | -DMBA/TPA model; 100 or 500 nmol of herbacetin applied to dorsal mouse skin at 30 min before TPA treatment. -solar–UV induced-skin tumor mouse model; after 20 weeks later, herbacetin 100 or 500 nmol for an additional 7 weeks -xenograft model; herbacetin 0.2 and 1 mg/kg; i.p. injected three times per week for 15 days | skin papillomas↓, tumor volume↓, Ki67↓, pAKT↓, pGSK3β↓, pRSK↓, ODC↓ | [38] |
Luteolin | Reseda luteola | Melanoma | Female BALB/c -nude mice with A375 cells, 1 × 107 | 100 mg/kg/day, i.p. for 22 days | tumor growth↓ PI3K/AKT↓, MMP-2↓, MMP-9↓ | [41] |
Sinomenine | Sinomenium acutum | Melanoma | xenograft model; BALB/c nude mice (6-week-old) by subcutaneously injection with B16-F10 cells | 100 mg/kg/day; s.c., daily for 35 days. | tumor weight↓, tumor volume↓, Ki67↓, PCNA↓ | [45] |
Syringic acid | Euterpe oleracea, Rhus javanica | non-melanoma | SKH-1 hairless mouse, UVB (0.2 J/cm2) exposure (three times per week for 22 weeks) | 0.2 or 1 mM per mouse in 200 μL acetone on the dorsal surface 1 h before UVB irradiation | UVB-induced skin tumor↓, COX-2↓, MMP-13↓, | [48] |
Ginkgo biloba Exocarp Extract | C57BL/6J female mice (6-week-old) by subcutaneously injection with B16-F10, 2.0 × 106 cells | 50, 100, 200 mg/kg by intragestic gavage, once a day for 17 days | tumor growth↓, lung metastasis↓, MMP-9↓ | [51] | ||
α-Mangostin | pericarp of mangosteen | Skin cancer | DMBA (60 μg)/TPA (4 μg) induced skin carcinogenesis model in ICR female mice, once a week for 20 weeks | 5 and 20 mg/kg, (dissolved in 0.2 mL olive oil) once a day, starting from the day after TPA was topically applied, i.p. for 20 weeks | Skin papilloma↓, growth↓, LC3↑, LC3-II↑, Beclin1↑, LC3-I↓, p62↓, Bax↑, cleaved caspase-3↑, cleaved PARP↑, Bad↑, Bcl-2↓, Bcl-xl↓, apoptosis↑, p-PI3K↓, p-AKT↓, p-mTOR↓ | [54] |
Silibinin and its 2,3-dehydro-derivative | Silybum marianum (L.) Gaertn., Asteraceae | BCC | ectopic allograft model; five weeks old nude mice (Foxn1nu/nu) by subcutaneously injection with 1 × 106 ASZ cells | silibinin (200 mg/kg in 0.5% CMC) or DHS (200 mg/kg); oral administration, 6 days per week for a total of 7 weeks | tumor growth↓, PCNA↓, cyclin D1↓, proliferation↓, NF-κB↓, AP-1↓, c-Fos↓ | [56] |
Curcumin | rhizome of Curcuma longa | Melanoma | BALB/c nude female mice (6-week-old) by subcutaneously injection with A375 cells (1 × 107/mL) | 25 mg/kg by i.p. injections, every day for 3 weeks | growth↓ | [60] |
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Hwang, S.-Y.; Chae, J.-I.; Kwak, A.-W.; Lee, M.-H.; Shim, J.-H. Alternative Options for Skin Cancer Therapy via Regulation of AKT and Related Signaling Pathways. Int. J. Mol. Sci. 2020, 21, 6869. https://doi.org/10.3390/ijms21186869
Hwang S-Y, Chae J-I, Kwak A-W, Lee M-H, Shim J-H. Alternative Options for Skin Cancer Therapy via Regulation of AKT and Related Signaling Pathways. International Journal of Molecular Sciences. 2020; 21(18):6869. https://doi.org/10.3390/ijms21186869
Chicago/Turabian StyleHwang, Sun-Young, Jung-Il Chae, Ah-Won Kwak, Mee-Hyun Lee, and Jung-Hyun Shim. 2020. "Alternative Options for Skin Cancer Therapy via Regulation of AKT and Related Signaling Pathways" International Journal of Molecular Sciences 21, no. 18: 6869. https://doi.org/10.3390/ijms21186869
APA StyleHwang, S.-Y., Chae, J.-I., Kwak, A.-W., Lee, M.-H., & Shim, J.-H. (2020). Alternative Options for Skin Cancer Therapy via Regulation of AKT and Related Signaling Pathways. International Journal of Molecular Sciences, 21(18), 6869. https://doi.org/10.3390/ijms21186869