Abstract
Sonodynamic therapy (SDT) is a noninvasive method for cancer treatment based on selective activation of a sonosensitiser by ultrasound (US), which results in the generation of reactive oxygen species (ROS) and cancer cell death. SDT uses a similar approach to photodynamic therapy (PDT), but can overcome the main drawback of PDT, i.e., poor tissue penetration of light. This research work investigated the anticancer effect of SDT on various two- (2D) and three-dimensional (3D) in vitro tumour models, using PDT as a reference treatment. Sonodynamic experiments were performed with pulsed US, specifically with shock waves (SW) and the prodrug 5-aminolevulinic acid (Ala), which is converted—at the mitochondrial level—into the sonosensitiser protoporphyrin IX (PPIX). SW-mediated PPIX sonodynamic activation resulted in a significant decrease in cell proliferation, especially on human fibrosarcoma (HT-1080) cells, where PPIX accumulation was higher compared to human melanoma (A2058) and neuroblastoma (SH-SY5 Y) cells. Moreover, SW-mediated SDT showed significant ROS generation, cell line-dependent in its amount, probably due to differences in Ala-induced PPIX synthesis. In all cancer cell lines, apoptosis was highlighted as the main cancer cell death pathway determined by SW-mediated SDT, along with significant cytochrome c release, and a consequent increase in DNA damage. The efficacy of SDT with SW and Ala in halting cancer cell proliferation was also confirmed in 3D cancer spheroids. The present study suggests that SW-mediated SDT is a valuable approach to slow down tumour proliferation, thus opening an innovative scenario in cancer treatment.
Highlights
The biomedical applications of ultrasound (US) have evolved from its ubiquitous clinical use as an imaging tool to include an expanding array of therapeutic capabilities for treating cancer [1]
Even if the effectiveness of sonodynamic therapy (SDT) has been demonstrated in several tumour models, there is still limited knowledge of the specific mechanism of interaction between the sonosensitiser and US in tumour tissues, it seems that inertial cavitation plays a crucial role
As it is established that different morphological and cellular features of tumour cells can influence the therapeutic results [19], in this study, we considered three different human cancer cell lines, namely melanoma, fibrosarcoma and neuroblastoma, grown as 2D and 3D cell cultures, in order to investigate the SDT anticancer activity, by combining shock waves (SW) with the sonosensitiser protoporphyrin IX (PPIX) derived from the mitochondrial metabolisation of the prodrug 5-aminolevulinc acid (Ala)
Summary
The biomedical applications of ultrasound (US) have evolved from its ubiquitous clinical use as an imaging tool to include an expanding array of therapeutic capabilities for treating cancer [1]. The energy released by US-induced collapsing bubbles, in the phenomenon of inertial cavitation, generates high temperature and pressure which provide adequate conditions for pyrolysis, generating reactive oxygen species (ROS) such as hydroxyl radicals (·OH) [4]. Even if the effectiveness of SDT has been demonstrated in several tumour models, there is still limited knowledge of the specific mechanism of interaction between the sonosensitiser and US in tumour tissues, it seems that inertial cavitation plays a crucial role. In these terms, the peak wave pressure of US and the US insonation technique represent the most important parameters recruited to generate inertial cavitation
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