Inhibition of Macropinocytosis Enhances the Sensitivity of Osteosarcoma Cells to Benzethonium Chloride

Abstract

Osteosarcoma (OS) is a primary malignant tumor of bone. Chemotherapy is one of the crucial approaches to prevent its metastasis and improve prognosis. Despite continuous improvements in the clinical treatment of OS, tumor resistance and metastasis remain dominant clinical challenges. Macropinocytosis, a form of non-selective nutrient endocytosis, has received increasing attention as a novel target for cancer therapy, yet its role in OS cells remains obscure. Benzethonium chloride (BZN) is an FDA-approved antiseptic and bactericide with broad-spectrum anticancer effects. Here, we described that BZN suppressed the proliferation, migration, and invasion of OS cells in vitro and in vivo, but simultaneously promoted the massive accumulation of cytoplasmic vacuoles as well. Mechanistically, BZN repressed the ERK1/2 signaling pathway, and the ERK1/2 activator partially neutralized the inhibitory effect of BZN on OS cells. Subsequently, we demonstrated that vacuoles originated from macropinocytosis and indicated that OS cells might employ macropinocytosis as a compensatory survival mechanism in response to BZN. Remarkably, macropinocytosis inhibitors enhanced the anti-OS effect of BZN in vitro and in vivo. In conclusion, our results suggest that BZN may inhibit OS cells by repressing the ERK1/2 signaling pathway and propose a potential strategy to enhance the BZN-induced inhibitory effect by suppressing macropinocytosis.

Hydroxysafflor yellow A induced ferroptosis of Osteosarcoma cancer cells by HIF-1α/HK2 and SLC7A11 pathway

“…The traditional clinical treatment schemes mainly include preoperative chemotherapy, surgical limb salvage, and postoperative adjuvant chemotherapy [ 30 ]. However, in the last 20 years, the average survival rate of patients has remained stable at 65%–70% with no significant improvement [ 31 ]. It is highly sensitive to a variety of chemotherapy drugs, such as cisplatin, adriamycin, cyclophosphamide, etc., but it is easy to become resistant [ 32 ].…”

Pleiotropic physiological functions of Piezo1 in human body and its effect on malignant behavior of tumors

“…To adapt to this extreme environment, tumor cells often reprogram their cellular metabolism to take up essential nutrients from the nutritionally deprived environment and adjust intracellular metabolic pathways to supply the more important biological processes ( Pavlova Natalya and Thompson, 2016 ). Macropinocytosis is an important non-selective extracellular amino acid uptake pathway, which has been reported in tumor cells ( Del Bello et al, 2022 ; Xia et al, 2023 ) and even tumor stromal cells ( Zhang et al, 2021 ). Macropinocytosis is dependent on the formation of peripheral folds, whose formation and migration are regulated by actin ( Isogai et al, 2015 ).…”

A Novel Paclitaxel Derivative for Triple-Negative Breast Cancer Chemotherapy

“…Most chemotherapeutic drugs inhibit tumor growth by inducing apoptosis in cancer cells [35]. The apoptotic effect of PTX-TTHA on TNBC cells was determined using flow Transmission electron microscopy was used to visualize the interior ultrastructure changes of cells [37] treated with 0.1 nM PTX or PTX-TTHA for 48 h. Untreated MDA-MB-231 cells contained intact and uniform nuclei, with no apoptotic vesicles (Figure 3A,D). In contrast, remarkable cellular apoptosis-related characteristics were observed in both PTX-treated and PTX-TTHA-treated MDA-MB-231 cells, with the appearance of many vacuoles and high-density structures, as well as chromatin condensation and margination (Figure 3B,C,E,F).…”