A PTEN Inhibitor Displays Preclinical Activity Against Hepatocarcinoma Cells

Phosphatase and tensin homolog (PTEN) gene is considered a tumor suppressor gene. However, PTEN mutations rarely occur in hepatocellular carcinoma (HCC), whereas heterozygosity of PTEN, resulting in reduced PTEN expression, has been observed in 32\u201344% of HCC patients. In the present study, we investigated the effects of the small molecule PTEN inhibitor VO-OHpic in HCC cells. VO-OHpic inhibited cell viability, cell proliferation and colony formation, and induced senescence-associated \u3b2-galactosidase activity in Hep3B (low PTEN expression) and to a lesser extent in PLC/PRF/5 (high PTEN expression) cells, but not in PTEN-negative SNU475 cells. VO-OHpic synergistically inhibited cell viability when combined with PI3K/mTOR and RAF/MEK/ERK pathway inhibitors, but only in Hep3B cells, and significantly inhibited tumor growth in nude mice bearing xenografts of Hep3B cells. Therefore, we demonstrated for the first time that VO-OHpic inhibited cell growth and induced senescence in HCC cells with low PTEN expression, and that the combination of VO-OHpic with PI3K/mTOR and RAF/MEK/ERK inhibitors resulted in a more effective tumor cell kill. Our findings, hence, provide proof-of-principle evidence that pharmacological inhibition of PTEN may represent a promising approach for HCC therapy in a subclass of patients with a low PTEN expression

STUDY OF THE DISCREPANCY BETWEEN ANALYTICAL CALCULATIONS AND THE OBSERVED BIOLOGICAL EFFECTIVENESS IN PROTON BORON CAPTURE THERAPY (PBCT)

A work recently published experimentally demonstrates an increase in the radiobiological efficacy of clinical proton beams when a tumour is treated in the presence of a concentration of 11B. The paper, for the first time, demonstrates the potential role of the p+11B to 3{\alpha} (for brevity, p-B) reaction in the biological enhancement of proton therapy effectiveness. The work reports robust experimental data in terms of clonogenic cell survival and chromosomal aberrations and unambiguously shows the presence of an enhancement when cells were exposed to a clinical proton beam subject to treatment with sodium boroncaptate (BSH). Moreover, the greater occurrence of complex-type chromosomal exchanges points to the effect as due radiation of a LET (Linear Energy Transfer) greater than that of protons alone, possibly the alpha particles generated by the reaction. At the same time, we emphasized that analytical calculations, performed on the basis of the well-known total production cross section data, are not able to explain the effect in a macroscopic way, i.e. solely in terms of a trivial increase in the total dose released in the cells by the alpha-particles. In this paper, thanks to simulations and analytical calculations, we will discuss the theoretically expected alpha particle yield and the corresponding LET and RBE (Relative Biological Effectiveness) increase related to the 11B presence. We conclude that a mere calculation based on the classical concepts of integral Dose, and average LET and RBE cannot be used to justify the observed radiobiological phenomena. We, therefore, suggest that micro- and nano-dosimetric aspects must be taken into account

Multicenter evaluation of hypoxia effects on OER and RBE of charged particles on glioblastoma cell lines

CERVOXYInternational audienc

High-Intensity Focused Ultrasound- and Radiation Therapy-Induced Immuno-modulation: Comparison and Potential Opportunities

In recent years, high-intensity focused ultrasound (HIFU) has emerged as a new and promising non-invasive and non-ionizing ablative technique for the treatment of localized solid tumors. Extensive pre-clinical and clinical studies have evidenced that, in addition to direct destruction of the primary tumor, HIFU-thermoablation may elicit long-term systemic host anti-tumor immunity. In particular, an important consequence of HIFU treatment includes the release of tumor-associated antigens (TAAs), the secretion of immuno-suppressing factors by cancer cells and the induction of cytotoxic T lymphocyte (CTL) activity. Radiation therapy (RT) is the main treatment modality used for many types of tumors and about 50% of all cancer patients receive RT, often used in combination with surgery and chemotherapy. It is well known that RT can modulate anti-tumor immune responses, modifying micro-environment and stimulating inflammatory factors that can greatly affect cell invasion, bystander effects, radiation tissue complications (such as fibrosis), genomic instability and thus, intrinsic cellular radio-sensitivity. To date, various combined therapeutic strategies (such as immuno-therapy) have been performed in order to enhance RT success in treating locally advanced and recurrent tumors. Recent works suggested the combined use of HIFU and RT treatments to increase the tumor cell radio-sensitivity, in order to synergize the effects reaching the maximum results with minimal doses of ionizing radiation (IR). Here, we highlight the opposite immuno-modulation roles of RT and HIFU, providing scientific reasons to test, by experimental approaches, the use of HIFU immune-stimulatory capacity to improve tumor radio-sensitivity, to reduce the RT induced inflammatory response and to decrease the dose-correlated side effects in normal tissues