We studied a role of the inducible heat shock protein 70 (Hsp70) in cellular response to radiosensitizing treatments with inhibitors of the heat shock protein 90 (Hsp90) chaperone activity. Cell lines derived from solid tumors of different origin were treated with the Hsp90 inhibitors (17AAG, geldanamycin, radicicol, NVP-AUY922) or/and γ-photon radiation. For comparison, human cells of the non-cancerous origin were subjected to the same treatments. We found that the Hsp90 inhibitors yielded considerable radiosensitization only when they cause early and pronounced Hsp70 induction; moreover, a magnitude of radiosensitization was positively correlated with the level of Hsp70 induction. The quantification of Hsp70 levels in Hsp90 inhibitor-treated normal and cancer cells enabled to predict which of them will be susceptible to any Hsp90-inhibiting radiosensitizer as well as what concentrations of the inhibitors ensure the preferential cytotoxicity in the irradiated tumors without aggravating radiation damage to adjacent normal tissues. Importantly, the Hsp70 induction in the Hsp90 inhibitor-treated cancer cells appears to be their protective response that alleviates the tumor-sensitizing effects of the Hsp90 inactivation. Combination of the Hsp70-inducing inhibitors of Hsp90 with known inhibitors of the Hsp induction such as quercetin, triptolide, KNK437, NZ28 prevented up-regulation of Hsp70 in the cancer cells thereby increasing their post-radiation apoptotic/necrotic death and decreasing their post-radiation viability/clonogenicity. Similarly, co-treatment with the two inhibitors conferred the enhanced radiosensitization of proliferating rather than quiescent human vascular endothelial cells which may be used for suppressing the tumor-stimulated angiogenesis. Thus, the easily immunodetectable Hsp70 induction can be a useful marker for predicting effects of Hsp90-inhibiting radiosensitizers on tumors and normal tissues exposed to ionizing radiation. Moreover, targeting the Hsp70 induction in Hsp90 inhibitor-treated cancer cells and tumor vasculature cells may beneficially enhance the radiosensitizing effect.
Introduction. Testicular germ cell tumor is a relatively rare disease. Its high social significance is due to the fact that this pathology occurs in young patients. The standard schemes of polychemotherapy determine the potential possibility of effective treatment for most of the patients even with an advanced disease. Several circulating markers (alpha-fetoprotein, human chorionic gonadotropin and lactate dehydrogenase) are being used for therapy monitoring, but the low diagnostic specificity of these molecules determines the need to develop new approaches. Over the past years, circulating microRNA, for instance miR-371a-3p, appeared to be promising marker for testicular germ cell tumor monitoring. However, to develop and to implement in practice the microRNA-based diagnostic technologies, it’s necessarily to understand the features of the microRNA expression alterations specific for different histological types of testicular germ cell tumor.The study objective – to evaluate changes in the expression of several potential marker microRNA molecules (miR-302/ miR-367, miR-371/miR-373) in testicular germ cell tumor samples of various histological types.Materials and methods. Testicular germ cell tumor samples (n = 61), including seminomas, embryonic carcinomas, post-pubertal teratomas, yolk sac tumors, chorioncarcinomas, and corresponding normal tissue samples (n = 61) were included in the study. The analysis of selected miRNA expression was performed by reverse transcription and polymerase chain reaction.Results. We identified the changes in the expression profile of the miR-302/miR-367 cluster typical for semines, embryonic carcinomas, post-pubertal teratomas, yolk sac tumors and chorioncarcinomas, as well as changes in the expression profile of the miR-371/miR-373 cluster, universal for all histotypes except chorioncarcinomas. Inhibition of miR-10b and miR-145 expression in semines, embryonic carcinomas, and post-pubertal teratomas was demonstrated.Conclusion. Activation of miR-302b, miR-302d, miR-371a expression and inhibition of miR-10b, miR-145 expression in the tissue of the most common variants of testicular germ cell tumor is a characteristic feature of these tumors. The detected changes are significant and can lead to corresponding changes in the profile of circulating microRNAs.
Retinoblastoma is one of the most common retinal tumors in young children. Current early diagnostic and treatment strategies focus on the possibility to implement eye-preserving therapies. The 5-year overall survival for children with retinoblastoma is now 100%. First-line eye removal is recommended in extensive intraocular seeding and poor visual prognosis. The volume of adjuvant therapy is based on the histological risk factors for disease progression. This paper discusses the algorithms to determine risk factors and further systemic treatment strategy in several large study groups. Eye and even vision preservation is now possible in at least 65–75% of retinoblastoma patients. The paper also describes in detail the methods of locally administering chemotherapy which are considered eye-preserving treatment options, i.e., selective intra-arterial chemotherapy and intravitreal chemotherapy. Various physical methods of eye-preserving treatment which underwent significant development over the past decade are highlighted. In conclusion, the authors emphasize that retinoblastoma survivors, their siblings and offspring should be carefully monitored.Keywords: children, retinoblastoma, enucleation, polychemotherapy, selective intra-arterial chemotherapy, intravitreal chemotherapy, laser photocoagulation, transpupillary thermotherapy, cryotherapy, brachytherapy, monitoring.For citation: Ivanova S.V., Kuleva S.A., Sadovnikova N.N. et al. Retinoblastoma. Part 2. Treatment strategies for intraocular retinoblastoma. Russian Journal of Clinical Ophthalmology. 2020;20(4):197–203. DOI: 10.32364/2311-7729-2020-20-4-197-203.
Over the past two decades, mucormycosis has firmly taken 3rd place among invasive mycoses after candidiasis and aspergillosis in patients with oncohematological diseases. The article presents a clinical case of disseminated mucormycosis that developed in a child with nonHodgkin’s lymphoma on the background of deep immunosuppression.
In addition to the typical signs, what are the pallor of the skin and mucous membranes, frequent, weak pulse, fainting, etc., internal bleeding that occurs as a result of rupture of the fetus during an ectopic pregnancy is accompanied by other, no less characteristic phenomena from various systems organism, which sometimes make it possible to timely confirm or establish a diagnosis and differentiate this suffering from other similar painful conditions.
We propose to combine small molecule inhibitors of the chaperone activity of heat shock proteins (Hsps) with inhibitors of the Hsp expression for better targeting tumors. Our approach is based on such known facts: (i) cancer cells are addicted to the chaperone activity of Hsp90 and Hsp70, and (ii) inhibition of the Hsp90/Hsp70 chaperone activity in cancer cells leads to the HSF1-mediated induction of additional Hsps that can impair antitumor effects of the chaperone inactivation.Here we examined effects of inhibitors of the Hsp90 chaperone activity (17AAG, AUY922), an inhibitor of the Hsp70 chaperone activity (pifithrin-m) and inhibitors of the Hsp induction (quercetin, KNK437, triptolide, NZ28) on the tumor cell sensitivity to gamma-photon radiation (2-8 Gy) and conventional drugs such as doxorubicin and paclitaxel. It was found that pretreatments of cancer cells derived from human solid tumors of various localization (uterus, breast, thyroid and others) with 17AAG or AUY922 and/or pifithrin-m sensitized them to the cytotoxic action of doxorubicin, paclitaxel and gamma-radiation. Importantly, the sensitizing effects became significantly enhanced in the case of combination of AUY922 and pifithrin-m with quercetin or KNK437, or triptolide, or NZ28 added in non-toxic concentrations. Those sensitizing effects were manifested in 3-4-fold decrease in the values of IC50 for doxorubicin and paclitaxel, and 1.5-2-fold increase in the radiation dose enhancement factors (DEFs) counted from curves of the postradiation cell survival (see for example Table ). The data obtained have to motivate development of pharmacological inhibitors of the Hsp expression which could be combined with inhibitors of the chaperone activity of Hsp90 or Hsp70 for sensitizing malignancies to chemotherapy and radiotherapy.
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