Targeting Hsp90 in urothelial carcinoma

Abstract

Urothelial carcinoma, or transitional cell carcinoma, is the most common urologic malignancy that carries significant morbidity, mortality, recurrence risk and associated health care costs. Despite use of current chemotherapies and immunotherapies, long-term remission in patients with muscle-invasive or metastatic disease remains low, and disease recurrence is common. The molecular chaperone Heat Shock Protein-90 (Hsp90) may offer an ideal treatment target, as it is a critical signaling hub in urothelial carcinoma pathogenesis and potentiates chemoradiation. Preclinical testing with Hsp90 inhibitors has demonstrated reduced proliferation, enhanced apoptosis and synergism with chemotherapies and radiation. Despite promising preclinical data, clinical trials utilizing Hsp90 inhibitors for other malignancies had modest efficacy. Therefore, we propose that Hsp90 inhibition would best serve as an adjuvant treatment in advanced muscle-invasive or metastatic bladder cancers to potentiate other therapies. An overview of bladder cancer biology, current treatments, molecular targeted therapies, and the role for Hsp90 inhibitors in the treatment of urothelial carcinoma is the focus of this review.

Inhibition of heat-shock protein 90 sensitizes liver cancer stem-like cells to magnetic hyperthermia and enhances anti-tumor effect on hepatocellular carcinoma-burdened nude mice

“…Since the expression of HSP90 is mediated by thermoresistance, and many of HSP90's effector proteins are the protein kinases or transcription factors that regulate cell survival and apoptosis, the inhibition of HSP90 is predicted to make tumors more sensitive to hyperthermia therapy. 30 In addition, compared to normal tissues, the expression of HSP90 is prominently enhanced in tumor tissues, which suggests that HSP90 is one of the most promising targets to improve the efficacy of cancer treatments. The effects of HSP90 inhibition on tumor cells during hyperthermia therapy could effectively result in apoptosis at low temperatures without resulting in thermoresistance.…”

Geldanami̇si̇n Ve Tri̇kostati̇n A’nin İnsan Mesane Kanseri̇ Hücreleri̇ Üzeri̇ne Si̇nerji̇sti̇k Etki̇si̇

“…Erkeklerde prostat kanserinden sonra en sık rastlanan genitoüriner kanser türüdür. (1,2). Mesane kanser patogenezine bakıldığında tek bir tümör hücresinde çok sayıda genetik ve epigenetik alterasyonlar çoklu sinyal yolaklarının deregülasyonuna yol açmaktadır (2,3).…”

“…(1,2). Mesane kanser patogenezine bakıldığında tek bir tümör hücresinde çok sayıda genetik ve epigenetik alterasyonlar çoklu sinyal yolaklarının deregülasyonuna yol açmaktadır (2,3). Hücre proliferasyonundan sorumlu sinyal yolaklarındaki aberasyonlara ilaveten mesane kanserinin de içerisinde yer aldığı çok çeşitli kanser türünde ısı şok proteinleri (IŞP) aşırı ifadelenmektedir.…”

“…Bu nedenle araştırıcılar ısı şok proteinlerinin mesane kanserinin tanı ve prognozu için bir biyobelirteç olarak kullanılabilirliğine odaklanmışlardır. Isı şok proteinleri, immun sistemin önemli modülatörleri olmasından dolayı yeni mesane kanser tedavi stratejilerinin belirlenmesinde IŞP'leri önemli hedefler haline gelmektedir, özellikle modern kemoterapötikler ve radyoterapötikler ile birlikteki sinerjistik etkilerine odaklanılmıştır (2,4,5). Bu çalışmamızda amacımız, IŞP90 inhibitörü olan Geldanamisin'in (GA) tek başına ve/veya histon deasetilaz inhibitörü Trikostatin-A (TSA) ile birlikte kullanımının mesane kanser hücre hattı T24 hücreleri üzerine apoptotik etkisini incelektir.…”

Effects of gene polymorphisms in the endoplasmic reticulum stress pathway on clinical outcomes of chemoradiotherapy in Chinese patients with nasopharyngeal carcinoma

“…The SNP rs2074549 in the valosin-containing protein (VCP) gene is significantly associated with severe neutropenia in Chinese advanced NSCLC patients on platinum-based regimens [19] . As a molecular folding chaperone responding to ER stress, heat shock protein 90 beta family member 1 (HSP90B1) has been implicated in chemoresistance and radioresistance and often is an anticancer therapeutic target [20,21] . These findings suggest that the ER stress pathway may play an important role in cancer development and metastases.…”