Table 1 Summary of selected pharmacological inhibitors that have demonstrated potent inhibition of TDE biogenesis and release in pre-clinical studies
From: Developing anti-TDE vaccine for sensitizing cancer cells to treatment and metastasis control
Drug | Cellular targets and mechanisms of inhibition | Tumor model | Effect of TDE inhibition in tumor model | Refs. |
|---|---|---|---|---|
SyntOFF | Inhibition of the syndecan-syntenin-ALIX interactions which interferes with the formation of ILVs | MCF-7 Breast cancer cell line | Inhibition of proliferation, migration, and spheroid formation | |
Sulfisoxazole (SFX) | Inhibition of the binding of ET1 & ET2 to ETA leads to the downregulation of downstream effectors of MVB biogenesis and increases the fusion of MVBs and lysosomes. | MDA-MB 231 and 4T1 breast cancer cell lines and xenografts | Inhibition of tumor growth and metastasis, and prolongation of animal survival | |
Macitentan (MAC) | Inhibition of the binding of ET1 & ET2 to ETA leads to the downregulation of downstream effectors of MVB biogenesis and increases the fusion of MVBs and lysosomes. | MDA-MB 231 breast cancer cell line and xenografts | Reduction of TDE secretion and PD-L1 content of secreted EVs which enhanced CD8+ T cell cytotoxicity and synergized with PD-1/PD-L1 blockade | |
GW4869 | Attenuation of intraluminal ILV formation in MVBs by decreasing ceramide synthesis through inhibition of nSMase2 | PC-3M-2B4 and PC-3M-1E8 Prostate cancer cell lines | Inhibition of TDE release was associated with decreased M2 polarization of TAMs | |
Indomethacin | Impaired lipid transport by downregulating ABCA-3 expression | DLBCL cell lines SU-DHL-4, Balm3, OCI-Ly1 and OCI-Ly3 | Decreased EV secretion was associated with improved intracellular retention of doxorubicin and pixantrone, increasing their cytostatic effects | |
Atorvastatin | Reduction of cholesterol synthesis through the inhibition of HMG CoA reductase | SK-OV-3 ovarian cancer cell line and xenograft | Atorvastatin enhanced the cytotoxic effects of paclitaxel (PTX) in vitro and in vivo. | |
Tipifarnib | Modulation of multiple biogenesis processes including syndecan-syntenin-ALIX, nSMase, and ROCK-dependent pathways. | Prostate cancer cell lines (C4-2B and PC-3) and normal prostate cell line (RPWE-1) | Potent inhibition of TDE biogenesis in C4-2B and PC-3 cell lines. No inhibition was observed in the RPWE-1 prostate cell line. | |
Ketoconazole | Multiple targets and pathways including ESCRT-independent, ESCRT-dependent pathways, and Ras/ERK signaling pathways | Prostate cancer cell lines (C4-2B and PC-3) and normal prostate cell line (RPWE-1) | Potent inhibition of TDE biogenesis in C4-2B and PC-3 cell lines. No inhibition was observed in the RPWE-1 prostate cell line | |
BIM-1 | Inhibition of PKC, leading to decreased myosin contractility | PC-3 prostate cancer cell line | Potent inhibition of TDE and microvesicle release which resulted in increased drug retention and tumor cell apoptosis | |
Cl-amidine | Inactivation of PADs which block their ability to interact with cytoskeletal proteins essential for MV release. | PC-3 prostate cancer cell line | Potent inhibition of TDE and microvesicle release which resulted in increased drug retention and tumor cell apoptosis | |
Imipramine | Inhibition of acid sphingomyelinase (aSMase) | PC-3 prostate cancer cell line | Inhibition of the secretion of TDEs and MVs | |
Sulfasalazine | Inhibition of the cystine/glutamate anti-porter (system xc-) | Murine myeloma cells (5T33MM) and BMSCs | Inhibition of TDE secretion and overcoming bortezomib resistance | |
Mitomycin A | Inhibition of Ras/Raf/MEK/ERK1/2 signaling pathway | Prostate cancer cell line (C2-4B) | Inhibition of TDE secretion in C2-4B prostate cancer cell line |
