Mechanochemical Disruption Suppresses Metastatic Phenotype and Pushes Prostate Cancer Cells toward Apoptosis

Abstract

Chemical-based medicine that targets specific oncogenes or proteins often leads to cancer recurrence due to tumor heterogeneity and development of chemoresistance. This challenge can be overcome by mechanochemical disruption of cancer cells via focused ultrasound (FUS) and sensitizing chemical agents such as ethanol. We demonstrate that this disruptive therapy decreases the viability, proliferation rate, tumorigenicity, endothelial adhesion, and migratory ability of prostate cancer cells in vitro. It sensitized the cells to TNFR1-and Fas-mediated apoptosis and reduced the expression of metastatic markers CD44 and CD29. Using a prostate cancer xenograft model, we observed that the mechanochemical disruption led to complete tumor regression in vivo. This switch to a nonaggressive cell phenotype was caused by ROS and Hsp70 overproduction and subsequent impairment of NFkB signaling. FUS induces mechanical perturbations of diverse cancer cell populations, and its combination with agents that amplify and guide remedial cellular responses can stop lethal cancer progression.Implications: Mechanochemical disruption therapy in which FUS is combined with ethanol can be curative for locally aggressive and castration-resistant prostate cancer.

Phenotypic alterations in liver cancer cells induced by mechanochemical disruption

“…As we showed previously 16,36 , MCD of tumor tissue by a combination of PEI and HIFU increases the tissue ablation volume, reduces acoustic intensity, and decreases number of HIFU shots per tumor. It also decreases the aggressiveness of prostate cancer cells 28 and, as demonstrated in this work, HCC cells. In particular, MCD therapy prevents uncontrolled proliferation of HCC cells, sensitize the cells to apoptosis, and lowers their metastatic and tumorigenic potentials in vitro and in vivo .…”

“…This dose, however, is much less than the PEI clinical dose of 5 to 60 ml per 1 to 3 cm tumor, which would lead to fatal intoxication in mice. As tested in the prostate cancer study 28 and current work, the injection of 50 μL ethanol does not induce animal death and, in fact, it does not change the animal survival rate as compared to tumor-bearing animals in the control group.…”

“…Despite an eightfold increase in the TNFR1 expression level, liver cancer cells that survived MCD do not proliferate, suggesting that the NF-κB signaling pathway is impaired. We recently demonstrated that MCD leads to a loss of NF-κB p65 subunit in prostate cancer cells 28 . Also, the overproduction of ROS has been shown to inhibit metabolites in the NF-kB signaling pathway 46 .…”

“…S1 in ref. 28 ). This dose, however, is much less than the PEI clinical dose of 5 to 60 ml per 1 to 3 cm tumor, which would lead to fatal intoxication in mice.…”

Remote control of magnetic nanocomplexes for delivery and destruction of cancer cells

“…34,45 Overall these studies show that MCs can be proposed as useful tools under remote magnetic control for mechanochemical therapy. 46 The precise mechanism by which MCs pose the mechanochemical effects on cancer cells remains to be elucidated. A greater focus on the physicochemical properties of nanomaterials, such as the relation between magnetocrystalline anisotropy and magnetic interactions in tumors, could produce more findings for clinical implication.…”