Table 1.

Targeting MNK and/or eIF4E phosphorylation in different types of cancer

Cancer Types	Intervention Methods	Effects	Mechanisms	Reference
Breast cancer	Serine to Alanine mutation at eIF4E Serine 209	eIF4ES209A mice are resistant to lung metastases in a mammary tumor model (MMTV-PyMT)	Phosphorylation of eIF4E promotes EMT and metastasis via translational control of SNAIL and MMP-3	[31]
	MNK inhibitor CGP57380	CGP57380 inhibits proliferation of cell lines SKBr3, BT474, ZR75.1, T47D, and MDA-MB-231	CGP57380 may inhibit the synthesis of cyclin D1 by inhibiting MNK kinase activity	[43]
	MNK inhibitor CGP57380	CGP57380 reduces colony formation of AU565 cells	MNKs is activated in the HER2/Ras/Raf/ERK pathway and it correlates with HER2 overexpression	[63]
	MNK inhibitor CGP57380	CGP57380 inhibits proliferation of MDA-MB 468 and MDA-MB 231 cells	CGP57380 associates with an increase of E-cadherin and β-catenin protein levels by downregulating p-eIF4E levels	[64]
	Retinoic acid metabolism blocking agents (RAMBAs) VNLG-147, −152 and −153, etc	RAMBAs inhibited growth, colonization, invasion, and migration and induce apoptosis of MDA-MB-231 and MDA-MB-468 cells	RAMBA retinamides degrade MNK rather than inhibiting its kinase activity	[65]
	MNK inhibitor CGP57380	CGP57380 restored tamoxifen sensitivity	eIF4E phosphorylation is increased in tamoxifen-resistant breast cancers cell lines	[66]
	Chemotherapeutic drugs doxorubicin, cyclophosphamide, dasatinib and MNK inhibitor CGP57380	CGP57380 enhances response of LCC1 and LCC9 cells to chemotherapy	MNK inhibition abolishes chemotherapeutic drugs-mediated β-catenin activation in breast cancer cells	[67]
	MNK inhibitor CGP57380	CGP57380 decreased SUM149 cells dissemination within window chamber model with GFP-tagged SUM149	MNK signaling promotes XIAP expression and NFκB activity	[68]
	MNK inhibitors CGP57380 and cercosporamide	Synergistic combination of MNK1/2 and PI3K inhibitors slow the rate of cell migration in MDA-MB-231 cells	The combination of MNK1/2 and mTORC1/2 inhibition induces G1 cell cycle arrest	[69]
	Novel ferrocene analogues	Compound 5 reduces cell proliferation and the IC50 in MDA-MB-231 cells (triple negative breast cancer cells)	Novel ferrocene analogues-compound 5 inhibits MNK1/2 kinase activity	[70]
	MNK1/2 protein degraders, racemic VNLG-152	VNLG-152 exhibits remarkable antitumor and antimetastatic activities against the MDA-MB-231 cell line and patient-derived TNBC xenograft models	MNK-eIF4E signaling pathway regulates downstream factors involved in cell cycle regulation, apoptosis, pro-inflammatory cytokines/chemokines secretion, epithelial-mesenchymal transition (EMT) and metastasis	[71]
	MNK-7g containing thieno [2,3-d] pyrimidine scaffold	MNK-7g blocks the migration of MDA-MB-231 cells	MNK-7g targeting MNK1/2 does not affect other signaling pathways tested and have no adverse effects on cell viability	[72]
Ovarian cancer	MNK inhibitor CGP57380	CGP57380 significantly suppresses OVCAR-5 cell proliferation	MNK1 regulates the mRNA translation of proliferation-related proteins through phosphorylating eIF4E in ovarian cancer cell	[73]
	MEK inhibitor U0126	U0126 combined with chemotherapeutic agents significantly enhances growth inhibition and apoptosis induction of SK-OV-3 cells	Chemotherapy agents activate ERK/MNK/eIF4E in a MEK-dependent manner	[74]
Cervical cancer	MNK inhibitor CGP57380 or MNK siRNAs	CGP57380 is effective in inhibiting proliferation and migration, and inducing apoptosis in cervical cancer cells CaLo, SiHa and C-33A	CGP57380 or MNK siRNAs can effectively reduce the phosphorylation of eIF4E and β-catenin, thereby reducing β-catenin activity and Wnt target gene transcription levels in cervical cancer cells	[75]
Prostate cancer	Serine to Alanine mutation at eIF4E Serine 209	eIF4ES209A mice are resistant to tumorigenesis in a prostate cancer model.	eIF4E phosphorylation increases the translation efficiency of a subset of mRNAs encoding pro-tumorigenic factors	[30]
	Novel retinamides (NRs)	NRs induce cell cycle arrest, apoptosis, and inhibit proliferation and migration of PC-3, C4-2B and 22Rv1 cells	NRs target both AR signaling and eIF4E translation via enhancing AR and MNK degradation through ubiquitin-proteasome pathway	[76]
	VNHM-1–81, VNHM-1–66 VNHM-1–73	Retinamides inhibit cell proliferation and migration and induce apoptosis in MDA-MB-231 human breast and CWR22Rv1 prostate cancer sells	These novel C-4 azolyl retinamides (NRs) induce MNK1/2 degradation via the ubiquitin-proteasome pathway with resultant depletion of p-eIF4E	[77]
	Galeterone and VNPT55	VNPT55 profoundly inhibits migration and invasion of PC-3, DU145 and CWR22Rv1 cells	Galeterone and VNPT55 downregulate protein expression of several EMT markers (Snail, Slug, N-Cadherin, Vimentin and MMP-2/−9) via antagonizing the MNK-eIF4E axis	[78]
	MNK inhibitor CGP57380	CGP57380 sensitizes CRPC cells to RAD001 and bicalutamide	CGP57380 reduces eIF4E phosphorylation and sensitizes survivin levels to RAD001	[79]
	a novel retinamide VNLG-152	VNLG-152 suppresses growth and metastasis of aggressive CWR22Rv1 tumors xenograft	The retinamide VNLG-152 decreases cyclin D1 and Bcl-2, suppresses EMT in CWR22Rv1 tumors	[80]
Leukemia	MNK inhibitor CGP57380	CGP57380 enhances myeloid differentiation of HL60 and 32D cells	MNK1 expression is associated with high levels of c-Myc expression	[44]
	MNK inhibitor CGP57380 or MNK siRNAs	CGP57380 or MNK siRNAs enhances the suppressive effects of low cytarabine concentrations on CFU-L of U937 cells	MNK kinase is negatively regulated in the generation of chemotherapy-induced antileukemic responses	[81]
	MNK inhibitor CGP57380	CGP57380 significantly reduces serial replating efficiency of blast crisis (BC) progenitors and prevents BC granulocyte macrophage progenitors from serially transplanting immunodeficient mice	CGP57380 prevents β-catenin activation	[82]
	MNK inhibitor cercosporam-ide	Cercosporamide suppresses effects on primitive leukemic progenitors (CFU-L) of U937 cells and suppresses growth of MV4-11 AML xenograft tumors	Cercosporamide suppresses phosphorylation of eIF4E and exhibits antileukemic effects	[83]
	Selective MNK2 inhibitor (MNKI-85) and a dual-specific MNK1 and MNK2 inhibitor (MNKI-19)	MNKI-85 and MNKI-19 are effective in inhibiting the growth of FLT3- internal tandem duplication (ITDs) expressed AML cells	MNKI-19 and MNK-85 reduce the level of phosphorylated eIF4E, induce G1 phase cell cycle arrest and apoptosis	[84]
	Ribavirin	Ribavirin inhibits cell proliferation and induces apoptosis of K562 cells	Ribavirin reduces the expression of Mcl-1 at protein synthesis level but not mRNA transcriptional level by decreasing eIF-4E phosphorylation	[85]
	MNK inhibitor MNKI-8e and short hairpin RNA (shRNA) mediated knockdown	MNKI-8e and MNK shRNAs enhances the ability of cytarabine to induce apoptosis of MV4-11 AML cells	MNKI-8e and MNK shRNAs downregulates the expression of anti-apoptotic Mcl-1 protein	[86]
	Merestinib	Merestinib suppresses cell growth of AML patient-derived cells and tumor growth in a MM6 cell xenograft model	Merestinib blocks Mnk kinase activity and eIF4E phosphorylation in acute myeloid leukemia cells	[87]
	Niclosamide and dasatinib	The combination of niclosamide and dasatinib significantly inhibit proliferation and induces apoptosis in a panel of CML cell lines	Niclosamide can inhibit phosphorylation of Erk, MNK1 and eIF4E in CML cells	[88]
	MNK inhibitor CGP57380 and everolimus	CGP57380 produces a synergistic growth inhibitory effect with everolimus in T-cell acute lymphoblastic leukemia (T-ALL) cells	CGP57380 overcomes everolimus-mediated eIF4E phosphorylation and sensitizes T-ALL cells to everolimus	[89]
	N-phenyl-4-(1H-pyrrol-3-yl) pyrimidin-2-amine derivatives	Most of these compounds demonstrate potent anti-proliferative activity against MV4-11 AML cells	These compounds reduce eIF4E phosphorylation and induced apoptosis by down-regulating Mcl-1 and by cleaving PARP	[90]
Lymphoma	Serine to Alanine mutation at eIF4E Serine 209; an constitutively activated or kinase-dead form of MNK1	MNK1 activation promotes tumorigenesis and MNK1 repression inhibits tumor cell proliferation	eIF4E phosphorylation suppresses apoptosis by up-regulating the anti-apoptotic protein Mcl-1	[49]
	MNK inhibitor CGP57380	CGP57380 causes inhibition of cell proliferation and cell death in HKBML cell line	MNK inhibitor reduces cyclin D1 expression	[91]
	MNK inhibitor 4-Amino-5-(4-fluoroanilino)-pyrazolo[3,4-d] pyrimidine	MNK Inhibitor suppresses growth of cutaneous T-Cell lymphoma (CTCL) cells and displays a minimal pro-apoptotic effect	MNK inhibitor induces cell apoptosis	[27]
Pancreatic cancer	MNK inhibitor CGP57380 and ribavirin	CGP57380 and ribavirin significantly weaken Sox2-mediated repopulation of SW1990 and BxPc-3 cells	CGP57380 enhances tumor radiosensitivity by inhibiting eIF4E phosphorylation	[52]
	MNK inhibitor MNK-I and gemcitabine	MNK-I significantly increased cell death in MiaPaCa2 cells exposed to gemcitabine	MNK-I strongly reduces gemcitabine-induced eIF4E phosphorylation	[92]
	MNK inhibitor CGP57380	CGP57380 can reverse EMT, decrease migration,and limit growth of CD18-CR cells	CGP57380 increases E-cadherin, decreases vimentin and reduces migration of PDAC cells, decreases the protein expression of ZEB1 without reducing ZEB1 mRNA levels	[93]
	Gal/analogs (VNPT55, VNPP414 and VNPP433-3β)	Gal/analogs profoundly inhibit cell viability of gemcitabine-naive/resistance PDAC cell lines	Gal/analogs downregulate MNK1/2, peIF4E, NF-κB (p-p65), N-cadherin, MMP-1/−2/−9, Slug, Snail, CXCR4, β-Catenin, Nanog, BMI-1, Oct-4 and induced caspase 3-mediated cell-death	[94]
Lung cancer	MNK inhibitor CGP57380 and mTOR inhibitor RAD001	CGP57380 and RAD001 augment the antitumor efficacy through inhibiting proliferation and inducing apoptosis in A549 and H157 cells	CGP57380 suppresses eIF4E phosphorylation and sensitizes NSCLC cells to RAD001	[95]
	Rifabutin	Rifabutin is effectively against H3255, H1650 and H460 cells and H3255 xenograft mouse model through inhibiting proliferation and inducing apoptosis	Rifabutin suppresses eIF4E phosphorylation and decreases β-catenin activity	[96]
Hepatocellular carcinoma	MNK inhibitor cercosporamide	Cercosporamide selectively suppresses angiogenesis, growth and survival of HepG2, HuH6, SNU-182 and Hep3 B cells	Cercosporamide blocks eIF4E phosphorylation and selectively exhibits anti-HCC activities	[56]
Glioma	MNK1/2 double knockdown and MNK inhibitor CGP57380	MNK1 knockdown of U87MG cells shows reduced focus formation and enhanced apoptosis	eIF4E phosphorylation enhances the translation of pro-survival genes	[50]
	MNK inhibitor CGP57380 and RAD001	CGP57380 inhibits BS125 and LN319 cell growth and sensitizes GBM cells to rapamycin.	SMAD2-dependent TGF-β signaling pathway and vimentin expression are suppressed by CGP57380	[53]
	MNK inhibitor CGP57380 and RAD001	CGP57380 and RAD001 profoundly inhibit proliferation in U373, LN229, and U87MG cells and reduce tumor growth in U87MG-luc glioma cells xenograft mouse model	CGP57380 suppresses eIF4E phosphorylation and increases 4EBP1 binding to eIF4E combined with RAD001	[97]
	MNK inhibitor merestinib	Merestinib inhibited growth of 83Mes, MD30, and GBM43 cells and improved overall survival in the U87 cell xenograft mouse model	Merestinib blocks phosphorylation of eIF4E in established GBM cell lines and patient-derived glioma stem cells (GSCs)	[98]
	MNK inhibitor CGP57380 and temozolomide (TMZ)	CGP57380 sensitive U373, LN229 cells to chemotherapeutic drugs TMZ	CGP57380 reduces eIF4E phosphorylation and induces association of inactive MNK1 with eIF4G1	[99]
	MNK inhibitor CGP57380 or MNK1/2 siRNAs and arsenic trioxide (ATO)	CGP57380 sensitizes 83Mes cells to arsenic trioxide in neurosphere and apoptosis assays	CGP57380 suppresses MNK activation and eIF4E phosphorylation, which are activated by ATO	[100]
Medulloblastoma	MNK inhibitor CGP57380	CGP57380 and PI3Kα significantly reduce tumor formation and promote survival in subcutaneous and intracranial mouse D283 cell xenograft models	CGP57380 enhances the antineoplastic effects of PI3Kα inhibition by inhibiting MNK	[101]
Neurofibromin 1-mutant (NF1-mutant) cancers	Cabozantinib and MEK inhibitor PD-0325901 (PD901)	Cabozantinib cooperates with PD901 induces tumor regression in C57BL/6-Trp53tm1Tyj Nf1tm1Tyj (NPcis) mice	Cabozantinib suppresses eIF4ES209 phosphorylation in malignant peripheral nerve sheath tumors (MPNSTs) at even lower concentrations than CGP57380	[102]
Multiple myeloma (MM)	MNK inhibitor CGP57380; Serine to alanine mutation at eIF4E serine 209	CGP57380 prevents IL-6-induced stimulation of growth of ANBL-6 and 8226 MM cell lines; CGP57380 or curtailing eIF-4E phosphorylation with the phosphomutant will prevent MM growth in 8226 cell xenograft mice	CGP57380 or curtailing eIF-4E phosphorylation inhibit IL-6-induced MM cell expansion and gene expression involved in metabolic and proteotoxic responses	[103]
Nasopharyngeal Carcinoma	MNK inhibitor CGP57380	CGP57380 decreases proliferation, cell cycle progression, migration, invasion, and metastasis in NP69, CNE1, HNE1, HNE2, 5–8F, and 6–10B cells and CNE1 cells xenograft mice	GP57380 downregulates β-catenin in the nucleus	[45]
Thyroid cancer	MNK inhibitors CGP57380, cercosporamide and cisplatin	MNK inhibitors inhibit proliferation and induces apoptosis of ATC cells and enhances the effects of cisplatin in in vitro and in vivo	MNK inhibitors enhance the efficacy of cisplatin by inhibiting cisplatin-induced eIF4E phosphorylation.	[104]
	MNK inhibitor CGP57380 and MNK1/2 siRNA, BET inhibitors (BETis)	CGP57380 and MNK1/2 siRNA potentiate the effects of BETis at suppressing proliferation in K1, RO82-w-1, and FTC-133 cell lines and suppressing tumor growth in TBP-3868 thyroid cancer cells implanted mice	CGP57380 and MNK1/2 siRNA enhance the efficacy of BETis in suppressing proliferation of cancer cells in vitro and in a syngeneic mouse model by inhibiting MNKs	[105]