Table 6. Chemical nature, mode of action and effect of different EGFR, VEGF, PDGF, PI3K/AKT, mTOR and MMP inhibitors in glioma.

Drug	Chemical nature	Mode of action	Tumor type	Effect	Reference
Catanionic solid lipid nanoparticles (SLNs) loaded with doxorubicin	Anthracycline derivative. Dox-loaded catanionic SLNs (Dox–CASLNs) with surface anti-EGFR	Anti-EGFR	U87MG cell line	Reduced the cytotoxicity to human brain-microvascular endothelial cells and high targeting efficacy against the growth of GBM	88
DOX-loaded FA-PMs	Smart thermoresponsive micelle		C6 glioma rat tumor model	Significant accumulation of drug in tumor sites inhibiting tumor volume by ~83.9%	89
PLX4032 or Vemurafenib dabrafenib	Phenylpyridine	Inhibit BRAF V600E	Pilocytic astrocytoma	80% of patients showing either partial or complete remission, 74% reduction in disease progression or death, and a survival advantage over patients treated with dacarbazine alone	82
Sunitinib	Indoline	VEGF inhibitor	Pediatric tumor	Decreased plasma levels of endoglin, a marker of tumor-associated endothelial cells
Sorafenib	Diarylether	VEGF inhibitor PDGFR Raf	Pediatric patients with low grade astrocytomas	Phase II study Suspended due to excess progressive disease	76,82
Thalidomide	Isoindolone	Antiangiogenic	High grade glioma	Withdrawn from clinical use due to well characterised teratogenic effects	82
Lenalidomide	Isoindoline	Antiangiogenic	Recurrent primary CNS tumor	Increased haematological toxicity
PBTC-018	Phase I Trial of Lenalidomide (pediatric brain tumor consortium study)	Antiangiogenic	51 pediatric patients with recurrent, refractory, or progressive CNS tumors	Objective responses observed in children with low grade glioma
Imatinib mesylate (Gleevec®)	N-phenylbenzamide	PDGF inhibitor	Recurrent glioma	Penetrate BBB Decrease high interstitial fluid pressure in the tumor	74
Gefitinib (Iressa®)	Naphthyridines class Quinazolinamine	EGFR inhibitor	53 Recurrent GBM patients	Shows little effect on cells expressing the EGFRvIII mutation.
Erlotinib (Traceva®)	Quinazolinamine	EGFR inhibitor	GBM	Promising effects in GBMs where EGFRvIII and PTEN are coexpressed
AZD2171 (cediranib)	Diarylether	VEGFR inhibitor	Recurrent GBM	Strong antiedema effect and favorable PFS-6
Cetuximab	Monoclonal antibody. Peptide derivative	EGFR inhibitor Targeting RTKs	GBM	Prevent EGFR-mediated signal transduction by interfering with ligand binding and EGFR extracellular dimerization Increase in overall survival, but only in wild-type EGFR amplified GBM	75
RO4929097	Dibenzazepin	γ Secretase inhibitor	Types of glioma	Clinical trials
Lapatinib (GW572016)	Naphthyridines class. Quinazolinamine	EGFR+Erb-B2	U87 and M059K glioma cells	Considerable effects on proliferation, apoptosis and migration of glioma cells were observed	76
AEE788	Pyrimidin-4-amine	EGFR+VEGFR	GBM patients	Unacceptable toxicity and minimal activity
ZD6474 (Vandetanib)	Quinazolinamine	EGFR+VEGFR+RET	U251 cell line, xenograft	Autophagy was observed
Nimotuzumab	Humanized monoclonal antibody	EGFR	Glioma	In orphan status
Nilotinib	N-phenylbenzamide	PDGFR	U87 and LN827 cell line	Oral drug that has greater potency and selectivity for BCR-ABL than imatinib	76,90
Vatalanib	Phthalazine	PDGFR+VEGFR	Glioma	Influence angiogenesis and tumor growth through multiple targets and are currently in various stages of preclinical and clinical investigation	76
Dasatinib	Anilide	PDGFR+Src+cKit+Bcr-Abl	Malignant glioma	Phase trials
Tandutinib	Quinazolinamines	PDGFR+cKit+FLT-3	Malignant glioma	Phase trials
CP-673,451	Triazolo[4,5-d] pyrimidine	PDGFR	Rat glioma (C6 cell line)	Inhibits tumor PDGFR-beta phosphorylation, selectively inhibits PDGF-BB-stimulated angiogenesis in vivo, and causes significant tumor growth inhibition in multiple human xenograft models.	76,91
AMG706	Nicotinamide	PDGFR+VEGFR+cKit+Raf	Glioma	Inhibits angiogenesis and induces regression in tumor xenografts	92
Pazopanib	Aminobenzenesulfon amide	PDGFR+VEGFR+cKit	Malignant glioma	Influence angiogenesis and tumor growth through multiple targets and are currently in various stages of preclinical and clinical investigation	76
SUO11248	Indoline	PDGFR+VEGFR+cKit	Malignant glioma	Phase I trial
OSI-930	Thiophene drivative	PDGFR+VEGFR	Malignant glioma	Clinical investigation
TKI258	Benzimidazole-quinolinone compound	PDGFR+VEGFR	Malignant glioma	Clinical investigation
Aflibercept	Peptide	VEGF-A/B Ab	GBM patients	30% Therapeutic response
XL184	Quinoline	VEGFR+c-Met	GBM	Phase II study
Pazopanib	Aminobenzenesulfon amide	VEGFR, PDGFR, c-Kit	Malignant glioma	Phase II trials
Cediranib	Quinazoline	VEGFR+PDGFR+cKit	CNS tumor	Phase I trials
Bay549805		Raf	Recurrent or progressive malignant glioma	Phase I trials
AAL881		Raf, VEGFR	Glioblastoma cell lines and intracranial glioblastoma xenograft designs	Anti-proliferative activity
Torin-1	Pyridinonequinoline	mTORC kinase inhibitor	Glioma	Preclinical studies	82
WYE-354	Piperidinecarboxylate	mTORC kinase inhibitor	Glioma	Preclinical studies
XL765	Quinoxalinyl	Dual PI3K/mTOR inhibitor	Intracranial xenograft mouse model of high grade glioma	Potential antineoplastic activity
Substituted benzimidazole	Heterocyclic aromatic organic compound (benzene and imidazole)	Raf/MEK/ERK inhibitor	Astrocytoma	Antitumor activity	93
NVP-BEZ235	Imidazoquinoline derivative	Dual PI3K/mTOR inhibitor	(GBM) cells in vitro and in vivo	Blocked the growth of GBM elicited a prodifferentiation effect on A172 CSLCs	75
Enzastaurin	Bisindolylmaleimide	PKC-b2+Akt	Malignant glioma	55% PFS-6	76
Perifosine	Piperidinium	Akt	Malignant glioma	Induce cell death and reduce proliferation
Rapamycin (sirolimus)	Macrolide	mTOR inhibitor	SEGA	46% to 63% reduction in SEGA volume 52% to 82.6% reduction of tumor volume with bilateral SEGA	7,18
Everolimus (Afinitor RAD001)	40-O-(2-hydroxyethyl) derivative of sirolimus	mTOR inhibitor	SEGA	SEGA tumor volume was reduced more than 30% relative to baseline in 75% of patients, there was 50% or more reduction in tumor volume in 32% of patients with decrease in ventricular volume.
Temsirolimus (CCI-779)	42-[2,2-bis (hydroxymethyl)]-propionic ester of rapamycin	mTOR inhibitor	SEGA	Clinical trials	94
AP23573	Phosphorus-containing C43-modified rapamycin analogs	mTOR inhibitor	SEGA	Clinical trials
SI-27	Anti-MMP agent	MMP inhibitor	Clinically relevant glioma model	Restricted tumor angiogenesis to a level similar to that found in the normal contralateral hemisphere and successfully prolonged survival	75
PEX	210-amino acid fragment of MMP-2 and it corresponds to the hemopexin domain of MMP-2	MMP inhibitor	Glioma	Binds to integrin αvβ3 and is thought to competitively inhibit the binding of MMP-2 to integrin αvβ3	95
Cilengitide (EMD121974)	Selective inhibitor of the αvβ3 and αvβ5 integrins, cell surface adhesion molecules	MMP inhibitor	GBM Malignant gliomas	Facilitate endothelial proliferation and migration through the extracellular matrix	90
Angiostatin, Endostatin, Pigment epithelial-derived factor (PEDF) and Thrombospondin (TSP)-1 and -2	Endogenous inhibitors Taxol derivative	MMP inhibitor Targeting Tyr-3-octreotide (TOC) ligand of somatostatin receptors (SSTRs)	Animal models of malignant glioma Subcutaneous and orthotopic glioma model	Studies testing the potential therapeutic efficacy going on Enhanced efficiency of PSM by targeting both tumor cell and neovasculature. It also promoted drug's accumulation at tumor site.	95
Paclitaxel-loaded solid lipid nanoparticle modified with Tyr-3-octreotide (PSM)					96

PFS6-, 6 month progression-free survival; GBM, glioblastoma multiforme.