<p>Antitumor Activity of Cabazitaxel and MSC-TRAIL Derived Extracellular Vesicles in Drug-Resistant Oral Squamous Cell Carcinoma</p>

Abstract

Introduction TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) can induce apoptosis in a variety of cancer cells. However, drug resistance of tumor and short half-life seriously affects its clinical targeted therapy. Cabazitaxel (CTX) is a taxane drug, which can induce apoptosis or autophagy by inhibiting the phosphorylation of PI3K/Akt/mTOR and sensitive to some drug-resistant tumors. Therefore, we explored the possibility of developing a mesenchymal stem cell-derived exosomes (MSC-EXO) vector for oral squamous cell carcinoma (OSCC) to deliver CTX/TRAIL combinations. Methods After ultracentrifugation and dialysis, CTX/TRAIL loaded exosomes transfected MSC (MSCT)-derived exosome (EXO) (MSCT-EXO/CTX) were isolated and purified. The expression of CD63, CD9 and TRAIL was detected by BCA to confirm the origin of EXO. High-performance liquid chromatography (HPLC) was used to determine the drug loading of VPF and draw the in vitro release profile. MTT assay, flow cytometry and Western blot were used to detect the antitumor effect of MSCT-EXO/CTX in vitro. Subsequently, the antitumor effect of MSCT-EXO/CTX in vivo was verified by mouse model. Results The diameter of the membrane particles was about 60–150 nm. We have proved that the incorporation and release of CTX in MSCT-EXO can inhibit the activation of PI3K, Akt and mTOR, which is a possible synergistic mechanism of CTX. MSCT-EXO and CTX can induce the apoptosis of SCC25 tumor cells in a dose-dependent manner and exert a good synergistic effect in the proportion range of 10:1–5:1. The inherent activity of MSCT-EXO and the direct effect of MSCT-EXO/CTX on OSCC confirm that MSCT-EXO/CTX makes MSCT-EXO and CTX have an efficient synergistic effect and a highly effective pharmacological inhibition on cancer cells, as verified by the subsequent mouse model. MSCT-EXO/CTX showed the lowest relative tumor volume and the highest tumor inhibition rate (P<0.05) in vivo. Conclusion An MSCT-EXO-based CTX delivery system might be an effective anticancer method.

Mesenchymal stem cells-derived exosomes for drug delivery

“…More importantly, the use of paclitaxel was also significantly reduced [115]. In addition to breast cancer, MSC-EXOs loaded with anti-cancer drugs have also been used to treat other cancers, such as liver cancer, pancreatic cancer, and oral squamous cell carcinoma (Table 3) [116][117][118][119][120]. At present, because most anti-cancer drugs damage normal tissues and have strong side effects, loading drugs into MSC-EXOs for targeted delivery in vivo is mainly used to treat malignant tumors.…”

Impact of Non-Coding RNAs on Chemotherapeutic Resistance in Oral Cancer

“…Depletion of exosomal miR-196a restored cisplatin sensitivity in head and neck cancer cells. In contrast, normal cell-derived EVs have the potential to suppress tumor progression [ 212 , 213 , 214 , 215 ]. Notably, miR-200c was packaged into EVs derived from normal tongue epithelial cells (NTECs), which were transferred into docetaxel-resistant cells, and the transferred miR-200c influenced docetaxel resistance by inhibiting TUBB3 and PPP2R1B [ 212 ].…”

Roles of Mesenchymal Stem Cell-Derived Exosomes in Cancer Development and Targeted Therapy

“…In addition to the application of single drugs, the combined use of tumor necrosis factor-related apoptosisinducing ligand (TRAIL) and other drugs is also a popular research direction for tumor treatment. Qiu et al [82] obtained MSCT-EXs/CTX by combining CTX (a taxane drug) with TRAIL for the treatment of oral squamous cell carcinoma. The delivery system showed good antitumor activity in vitro; it effectively reversed the multidrug resistance of tumors and improved the sensitivity of chemotherapy drugs.…”