Pharmacological Inhibition of Exosome Machinery: An Emerging Prospect in Cancer Therapeutics

Abstract

Exosomes are nanocarriers that mediate intercellular communication, crucial for normal physiological functions. However, exponentially emerging reports have correlated their dysregulated release with various pathologies, including cancer. In cancer, from stromal remodeling to metastasis, where tumor cells bypass the immune surveillance and show drug resistivity, it has been established to be mediated via tumor-derived exosomes. Owing to their role in cancer pathogenicity, exosome-based strategies offer enormous potential in treatment regimens. These strategies include the use of exosomes as a drug carrier or as an immunotherapeutic agent, which requires advanced nanotechnologies for exosome isolation and characterization. In contrast, pharmacological inhibition of exosome machinery surpasses the requisites of nanotechnology and thus emerges as an essential prospect in cancer therapeutics. In this line, researchers are currently trying to dissect the molecular pathways to reveal the involvement of key regulatory proteins that facilitate the release of tumor-derived exosomes. Subsequently, screening of various molecules in targeting these proteins, with eventual abatement of exosome-induced cancer pathogenicity, is being done. However, their clinical translation requires more extensive studies. Here we comprehensively review the molecular mechanisms regulating exosome release in cancer. Moreover, we give insight into the key findings that highlight the effect of various drugs as exosome blockers, which will add to the route of drug development in cancer management.

Exosome Load Increases Systemically and Mediates Pro-tumoral M2 Macrophage Polarization in Lymphoma

“…Cancer cells are the transformed cells which show increased exosome biogenesis that carry oncogenic cargoes and alter the target cell behaviour towards pro-tumoral type [7]. Indeed, tumor-derived exosomes play a crucial role in governing aggressiveness and metastatic potential of cancer cells [5][6][7]. There are various molecular mechanisms which upregulate the exosome biogenesis machinery in cancer cells.…”

“…Accumulating evidence has established the role of tumor-derived exosomes in cancer-induced pathogenicity [5][6][7]. Importantly, there is increased biogenesis of exosomes within the tumor cells which are consequently release out into the circulation.…”

“…Several lines of evidence have shown that exosomes act as key drivers for pre-metastatic niche formation in various cancers. Importantly, tumor-derived exosomes, once they enter the circulation, reach at different sites throughout the body and establish an immunosuppressive pre-metastatic niche, where the tumor cells actually metastasize [7,33,34]. In this line, after evaluating increased exosome levels in serum, we were interested to investigate the status of exosomes at systemic level in tumor-bearing mice.…”

“…Cancer cells release an increased number of exosomes compared to non-transformed cells to promote its growth and metastasis [4]. Several reports have shown the role of tumor-derived exosomes in mediating pro-tumoral effects by reprogramming stromal cells to stimulate angiogenesis and activate immunosuppressive microenvironment [5][6][7]. Importantly, cancer development is critically governed by the immune response of the host.…”

Enhanced Delivery of Rose Bengal by Amino Acids Starvation and Exosomes Inhibition in Human Astrocytoma Cells to Potentiate Anticancer Photodynamic Therapy Effects

“…In cancer contexts, exosomes can influence the tumor spread through the intercellular transfer of oncogenic molecules [ 47 , 48 ] and/or conferring the resistance of malignant cells toward anticancer drugs through the packaging and the next extracellular release of the therapeutic cargoes [ 49 ]. Therefore, different strategies based on pharmacological blockage or inhibition of the exosomes machinery, in synthesis and release, have been proposed as cancer therapeutic advanced strategies [ 50 , 51 , 52 ]. To date, several pharmacological inhibitors of exosomes release, as neticonazole, ketotifen, cannabidiol and GW4869, have been successfully tested in different cells [ 53 ].…”