A New Strategy for Glioblastoma Treatment: In Vitro and In Vivo Preclinical Characterization of Si306, a Pyrazolo[3,4-d]Pyrimidine Dual Src/P-Glycoprotein Inhibitor.

Overexpression of P-glycoprotein (P-gp) and other ATP-binding cassette (ABC) transporters in multidrug resistant (MDR) cancer cells is responsible for the reduction of intracellular drug accumulation, thus decreasing the efficacy of chemotherapeutics. P-gp is also found at endothelial cells' membrane of the blood-brain barrier, where it limits drug delivery to central nervous system (CNS) tumors. We have previously developed a set of pyrazolo[3,4-d]pyrimidines and their prodrugs as novel Src tyrosine kinase inhibitors (TKIs), showing a significant activity against CNS tumors in in vivo. Here we investigated the interaction of the most promising pair of drug/prodrug with P-gp at the cellular level. The tested compounds were found to increase the intracellular accumulation of Rho 123, and to enhance the efficacy of paclitaxel in P-gp overexpressing cells. Encouraging pharmacokinetics properties and tolerability in vivo were also observed. Our findings revealed a novel role of pyrazolo[3,4-d]pyrimidines which may be useful for developing a new effective therapy in MDR cancer treatment, particularly against glioblastoma.

Potential of the dual mTOR kinase inhibitor AZD2014 to overcome paclitaxel resistance in anaplastic thyroid carcinoma.

PURPOSE: Anaplastic thyroid carcinoma (ATC) is an aggressive, chemo-resistant malignancy. Chemo-resistance is often associated with changes in activity of the RAS/MAPK/ERK and PI3K/AKT/mTOR pathways and/or a high expression of ATP binding cassette (ABC) transporters, such as P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). To assess the therapeutic efficacy in ATC of a combination of the dual mTOR kinase inhibitor vistusertib (AZD2014) and paclitaxel (PTX), we generated a new cell line (Rho-) via the selection of human thyroid carcinoma 8505C cells that exhibit a low accumulation of rhodamine 123, which serves as a P-gp and BCRP substrate. METHODS: Immunohistochemistry was used for P-gp and BCRP expression analyses in primary ATC patient samples. Spheroid formation and immunodeficient NSG mice were used for performing in vitro and in vivo tumorigenicity assays, respectively. MTT, flow-cytometry, fluorescent microscopy, cell death and proliferation assays, as well as migration, invasion and gelatin degradation assays, were used to assess the potential of AZD2014 to enhance the effects of PTX. ATC xenografts in SCID mice were used for evaluating in vivo treatment efficacies. RESULTS: Rho- cells were found to be 10-fold more resistant to PTX than 8505C cells and, in addition, to be more tumorigenic. We also found that AZD2014 sensitized Rho- cells to PTX by inhibiting proliferation and by inducing autophagy. The combined use of AZD2014 and PTX efficiently inhibited in vitro ATC cell migration and invasion. Subsequent in vivo xenograft studies indicated that the AZD2014 and PTX combination effectively suppressed ATC tumor growth. CONCLUSIONS: Our data support results from recent phase I clinical trials using combinations of AZD2014 and PTX for the treatment of solid tumors. Such combinations may also be employed for the design of novel targeted ATC treatment strategies.

Zuclopenthixol decanoate in pregnancy: successful outcomes in two consecutive offsprings of the same mother.

INTRODUCTION: Almost all individual antipsychotics are classified into the intermediate pregnancy risk category as no or limited data exist about human pregnancy outcomes. We presented the case of zuclopenthixol decanoate using in two successive pregnancies of the same woman, which had not been published in the available peer-reviewed literature. CASE REPORT: A middle-age female subject who suffered from schizophrenia received zuclopenthixol decanoate injection during her two consecutive pregnancies. About four and a half months before diagnosis of the first pregnancy (to approximately 3.5 years after psychosis emergence), zuclopenthixol decanoate (400 mg every other week, im injection) was introduced to the treatment protocol (due to previous non-compliance with haloperidol and risperidone). A significant clinical improvement was achieved and the dose during pregnancy was reduced to 200 mg once monthly and maintained to date. In both pregnancies the women gave birth to healthy girls who have been developing normally until now, at their ages of 6 months and of 3.5 years. During pregnancy and after giving birth to children the mothers' psychiatric status and her social functioning were significantly improved and are still stable. Close monitoring of the mother's health, a multidisciplinary approach to both her treatment and the monitoring of pregnancies as well as the complete compliance with the prescribed drug protocol were likely to be crucial for the therapeutic success. CONCLUSION: A favorable outcome of the present case suggests that the zuclopenthixol decanoate is a rational therapeutic option for pregnant women suffering from psychosis when the expected benefit exceed the potential risk, but a definitive evidence for its safety requires large, controlled studies.