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Review
. 2021 Jun 2;13(11):2765.
doi: 10.3390/cancers13112765.

Current Perspective on the Natural Compounds and Drug Delivery Techniques in Glioblastoma Multiforme

Tapan Behl  1 , Aditi Sharma  2 , Lalit Sharma  2 , Aayush Sehgal  1 , Sukhbir Singh  1 , Neelam Sharma  1 , Gokhan Zengin  3 , Simona Bungau  4   5 , Mirela Marioara Toma  4   5 , Daniela Gitea  4 , Elena Emilia Babes  6 , Claudia Teodora Judea Pusta  7 , Adrian Gheorghe Bumbu  8
Affiliations
Review

Current Perspective on the Natural Compounds and Drug Delivery Techniques in Glioblastoma Multiforme

Tapan Behl et al. Cancers (Basel). .

Abstract

Glioblastoma multiforme (GBM) is one of the debilitating brain tumors, being associated with extremely poor prognosis and short median patient survival. GBM is associated with complex pathogenesis with alterations in various cellular signaling events, that participate in cell proliferation and survival. The impairment in cellular redox pathways leads to tumorigenesis. The current standard pharmacological regimen available for glioblastomas, such as radiotherapy and surgical resection following treatment with chemotherapeutic drug temozolomide, remains fatal, due to drug resistance, metastasis and tumor recurrence. Thus, the demand for an effective therapeutic strategy for GBM remains elusive. Hopefully, novel products from natural compounds are suggested as possible solutions. They protect glial cells by reducing oxidative stress and neuroinflammation, inhibiting proliferation, inducing apoptosis, inhibiting pro-oncogene events and intensifying the potent anti-tumor therapies. Targeting aberrant cellular pathways in the amelioration of GBM could promote the development of new therapeutic options that improve patient quality of life and extend survival. Consequently, our review emphasizes several natural compounds in GBM treatment. We also assessed the potential of drug delivery techniques such as nanoparticles, Gliadel wafers and drug delivery using cellular carriers which could lead to a novel path for the obliteration of GBM.

Keywords: drug delivery techniques; flavonoids; glioblastoma multiforme; natural compounds; oxidative stress; therapeutic potential.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic representation of tyrosine kinase receptor activation and the major downstream signaling pathways involved in the pathogenesis of glioblastoma multiforme. Receptor tyrosine kinase are activated by ligand binding causing receptor dimerization and auto phosphorylation of the tyrosine kinase domain. This results in activation of two main downstream signaling pathways: Ras/ERK and PI3K/AKT. These receptors activate downstream signaling cascade that participates in cell survival, proliferation, angiogenesis. Legend: EGF—endothelial growth factor; EGFR—epidermal growth factor receptor; PDGF—platelet derived growth factor; PDGFR—platelet derived growth factor receptor; VEGF—vascular endothelial growth factor; VEGFR—vascular endothelial growth factor receptor; mTOR 1—mammalian target of rapamycin 1; HIF1α—hypoxia-inducible factor 1α; HSF—Heat shock protein; PTEN—phosphatase tensin homolog; MMP-2—matrix metallopeptidase 2; PI3K—Phosphoinositide 3-kinases; NFκB—nuclear factor κB; MAPK: Mitogen—activated protein kinase; MEK—MAPK extracellular signaling-regulated kinase; FOXO—Forkhead box O; FGFR—fibroblast growth factor receptor; BAX—BCL2-associated X protein; MDM2—murine double minute 2 ERK Extracellular regulated kinase; p53—tumor protein.
Figure 2
Figure 2
Schematic representation of ROS affecting different mechanistic pathways in cell proliferation and apoptosis in glioblastoma multiforme. EGFR—epidermal growth factor receptor; PDGFR—platelet-derived growth factor A receptor; VEGFR—vascular endothelial growth factor; CDK—cyclin-dependent kinase.
Figure 3
Figure 3
Signal transduction pathways targeted by phytoconstituents in glioblastoma. Apoptotic pathways are regulated by death receptor ligands (TRAIL and FAS). Once activated leads to the activation of FADD which further leads to the activation of caspase 8, 10, that targets BID protein inducing BAX oligomerization and release of cytochrome C from mitochondria along with activation of caspase 3 and 7 causing apoptosis. Another protein that regulates apoptosis is p53 which activates BAX. Receptor tyrosine kinase is activated by ligand binding causing receptor dimerization and auto phosphorylation of the tyrosine kinase domain. This results in activation of two main downstream signaling pathways: Ras/MAPK/ERK and PI3K/AKT. As these receptors activate downstream signaling cascade that participates in cell survival proliferation, angiogenesis and metastasis. Red arrows indicate inhibition and blue arrows indicate activation by phytoconstituents. Legend: TRAIL—Tumor necrosis factor-related apoptosis-inducing ligand; FADD—Fas-associated death domain; BID—B cell lymphoma-2-interacting domain; PARP—Poly (ADP-ribose) polymerase; EGF—endothelial growth factor; PDGF—platelet derived growth factor; HDF—hepatocyte growth factor; VEGF—vascular endothelial growth factor; EGFR—epidermal growth factor receptor; PDGFRα—platelet derived growth factor A receptor-α; FGFR—fibroblast growth factor receptor; PLC—Phospholipase C; PI3K—Phosphoinositide 3-kinases; mTOR 1—mammalian target of rapamycin 1; MAPK—mitogen-activated protein kinase; ERK—Extracellular-signal-regulated kinase; HIF1α—hypoxia-inducible factor 1α; MMP-2—matrix metallopeptidase 2; PTEN—phosphatase tensin homolog; PI3K—phospho inositol 3 Kinase; NFκB—nuclear factor κB.
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