Combination of NOS- and PDK-Inhibitory Activity: Possible Way to Enhance Antitumor Effects

We have previously demonstrated a high antitumor potential of NOS inhibitor T1023 (1-isobutanoyl-2-isopropylisothiourea hydrobromide): antitumor antiangiogenic activity in several animal tumor models and its ability to synergistically enhance the antitumor effects of bevacizumab, cyclophosphamide and γ-radiation. At the same time, rather rapid adaptation of experimental neoplasias to T1023 treatment was often observed. We attempted to enhance the antitumor activity of this NOS inhibitor by supplementing its molecular structure with a PDK-inhibiting fragment, dichloroacetate (DCA), which is capable of hypoxia-oriented toxic effects. We synthesized compound T1084 (1-isobutanoyl-2-isopropylisothiourea dichloroacetate). Its toxic properties, NOS-inhibiting and PDK-inhibiting activity in vivo, and antitumor activity on the mouse Ehrlich carcinoma model (SEC) were investigated in compare with T1023 and Na-DCA. We found that the change of the salt-forming acid from HBr to DCA does not increase the toxicity of 1-isobutanoyl-2-isopropylisothiourea salts, but significantly expands the biochemical and anti-tumor activity. New compound T1084 realizes in vivo NOS-inhibiting and PDK-inhibiting activity, quantitatively, at the level of the previous compounds, T1023 and Na-DCA. In two independent experiments on SEC model, a pronounced synergistic antitumor effect of T1084 was observed in compare with T1023 and Na-DCA at equimolar doses. There were no signs of SEC adaptation to T1084 treatment, while experimental neoplasia rapidly desensitized to the separate treatment of both T1023 and Na-DCA. The totality of the data obtained indicates that the combination of antiangiogenic and hypoxia-oriented toxic effects (in this case, within the molecular structure of the active substance) can increase the antitumor effect and suppress the development of hypoxic resistance of neoplasias. In general, the proposed approach can be used for the design of new anticancer agents.

From AVATAR Mice to Patients: RC48-ADC Exerted Promising Efficacy in Advanced Gastric Cancer With HER2 Expression

RC48-ADC is a novel humanized antibody specific for human epidermal growth factor receptor 2 (HER2)in conjugation with a microtubule inhibitor via a cleavable linker. This study was to evaluate the antitumor activity and mechanism of RC48-ADC in gastric cancer (GC) and explore the population that may benefit from RC48-ADC treatment. Four human GC cell lines and nine patient-derived xenograft (PDX) models were exploited to evaluate the antitumor effect of RC48-ADC or trastuzumab treatment in vitro and in vivo. The expression and phosphorylation of HER2 were assessed by immunohistochemistry (IHC) staining. Critical molecules of downstream PI3K/AKT and cell cycle and apoptosis signaling pathways were detected and quantified by immunoblotting. Combined with preliminary results of preclinical research, three patients with IHC3+, IHC2+/FISH+, and IHC2+/FISH- of HER2 were enrolled to verify the efficacy of RC48-ADC treatment in advanced GC. In vitro, RC48-ADC had superior antiproliferative effects in a dose-dependent manner on GC cells, especially on HER2-positive cells. In vivo, RC48-ADC exceeded trastuzumab in GC PDX models with HER2 expression, even in models with moderate to low expression of HER2. Further exploration of mechanism showed that RC48-ADC exerted the antitumor effect by inhibiting phosphorylation of HER2, inducing G2/M phase arrest and cell apoptosis in HER2-expressed PDX models. In clinical practice, RC48-ADC had satisfactory efficacy in HER2-positive and HER2 moderately expressed GC patients and demonstrated promising efficacy in HER2-positive patients who have progressed after anti-HER2 therapy. In conclusion, RC48-ADC exerted promising antitumor activity in HER2-positive as well as score of 2+ in IHC and ISH-negative AGC patients after progression of systematic treatment.

The Main Complications in Patients with Acute Leukemia during the Period of Myelotoxic Agranulocytosis

Annotation: Improvement of chemotherapeutic protocols and algorithms of accompanying treatment made it possible to increase the survival rate of patients with tumors of the blood system. Despite these advances, most of the cytostatic drugs currently widely used to treat patients with hemoblastosis, in addition to the antitumor effect, also cause myelosuppression and the development of granulocytopenia. Granulocytopenia is one of the main factors associated with infectious complications in patients with tumors of the blood system. The nature of infectious complications may differ depending on the duration of granulocytopenia. Keywords: agranulocytosis, immune agranulocytosis, myelotoxic agranulocytosis, acute lymphoblastic leukemias, level of persuasion of recommendations.

PPT1 Reduction Contributes to Erianin-Induced Growth Inhibition in Oral Squamous Carcinoma Cells

The anticancer properties of erianin have been recently discovered. However, the antitumor effect of erianin in oral squamous cell carcinoma (OSCC) remains unclear. In this study, we demonstrated that erianin can hamper OSCC cells growth both in vitro and in vivo. Erianin induced obvious G2/M arrest as well as apoptosis and gasdermin E (GSDME)-dependent pyroptosis in OSCC cells. Moreover, erianin increased autophagosome formation but decreased autolysosome function. Further study indicated that erianin significantly suppressed the expression of protein-palmitoyl thioesterase 1 (PPT1) and mTOR signaling. PPT1 has been reported to be a critical regulator of cancer progression by its modulation of autophagy and mTOR signaling. According to online databases, higher expression of PPT1 has been observed in OSCC tissues and is associated with poorer patient prognosis. As overexpression of PPT1 significantly reversed erianin-induced growth inhibition in OSCC cells, we identified the importance of PPT1 reduction in erianin-induced growth suppression. With the xenograft model, we confirmed the antitumor effect of erianin in vivo. Erianin efficiently decreased the tumor sizes, together with visibly reduced expression of PPT1 and phosphorylation of mTOR in the xenograft tumor tissues. Therefore, the present study indicated that erianin may be potentially used in OSCC therapy.