Heat shock protein inhibitors and vaccines as new agents in cancer treatment

Background: Heat shock proteins (HSP) play an essential role as molecular chaperones by assisting correct holding and folding in human cells. At the same time they present implications in tumor cell proliferation, differentiation, matrix invasion, angiogenesis, metastasis and cell death. They also possess the ability to present tumor molecules to the immune system and elicit an immune response. New agents targeting HSP, as anticancer treatment, are under clinical evaluation. Objective: The aim of this review is to explore the role of HSP90 inhibitors as anticancer agents as well as to evaluate the benefit from the use of autologous HSP vaccines in both the adjuvant setting and first-line treatment. Methods: The latest evidence regarding the use of geldanamycin analogues or newer water-soluble and synthetics molecules that inhibit the binding of HSP90 to client proteins was reviewed. Immunization using tumor-derived HSP in several cancer types was also evaluated. Conclusions: HSP90 inhibitors represent a promising therapeutic option although further evaluation in larger clinical trials is needed. On the other hand, HSP vaccination has already an established role in our armory against cancer.     

Geldanamycin as a Potential Anti-Cancer Agent: Its Molecular Target and Biochemical Activity

Heat shock protein 90 is one of the most abundantcellularproteins. Although its functions are still being characterized,itappears to serve as a chaperone for a growing list of cellsignaling proteins, including many tyrosine and serine/threoninekinases, involved in proliferation and/or survival. Thebenzoquinone ansamycin geldanamycin has been shown to bind toHsp90and to specifically inhibit this chaperone's function, resultinginclient protein destabilization. Its ability to simultaneouslystimulate depletion of multiple oncogenic proteins suggests thatgeldanamycin, or other molecules capable of targeting Hsp90 incancer cells, may be of clinical benefit.     

Monoenomycin: A Simplified Trienomycin A Analogue that Manifests Anticancer Activity

Macrocyclic natural products are a powerful class of lead-like chemical entities. Despite commonly violating Lipinski's "rule of 5", these compounds often demonstrate superior drug-like physicochemical and pharmacokinetic attributes when compared to their acyclic counterparts. However, the elaborate structural architectures of such molecules require rigorous synthetic investigation that complicates analogue development and their application to drug discovery programs. To circumvent these limitations, a conformation-based approach using limited SAR and molecular modeling was implemented to design simplified analogues of trienomycin A, in which the corresponding analogues could be prepared in a succinct manner to rapidly identify essential structural components necessary for biological activity. Trienomycin A is a member of the ansamycin family of natural products that possesses potent anticancer activity. These studies revealed a novel trienomycin A analogue, monoenomycin, which manifests potent anticancer activity.     

新抗病毒抗生素17997在大鼠体内药代动力学和组织分布研究

目的:建立大鼠血浆、胆汁和组织中17997的高效液相色谱测定法,研究大鼠静脉注射17997后药代动力学、组织分布和胆汁排泄,以及血浆蛋白结合率。方法:SD大鼠以 4或1 mg·kg~(-1)剂量尾静脉注射给药,按实验设计采集血样、组织、胆汁,用HPLC法测定药物浓度;血浆蛋白结合率用平衡透析法测定。结果:17997保留时间为约7.0min;大鼠静脉推注4mg·kg~(-1)17997后药代动力学参数如下:消除半衰期为75.71 min,C_0为4.51μg·mL~(-1),清除率为52.5mL·min~(-1)·kg~(-1),药时曲线下面积AUC为76.16 min·μg·mL~(-1);给药后15 min 17997在大鼠体内组织分布依次为肺16.55 μg·g~(-1)、十二指肠7.34 μg·g~(-1)、肝6.51 μg·g~(-1)、心4.18 μg·g~(-1)、肾3.31 μg·g~(-1)、脾3.12 μg·g~(-1)、胸腺1.83 μg·g~(-1)和淋巴结0.74 μg·g~(-1)。大鼠静脉推注4、1mg·kg~(-1)17997后24 h胆汁排泄率分别为(55.4±9.4)％和(58.8±11.8)％;大鼠血浆蛋白结合率为(92.27±2.91)％。结论:本实验建立了测定大鼠血浆、胆汁和组织中17997的高效液相色谱紫外检测法,操作便捷,高效灵敏,样品用量少。大鼠静脉推注17997后体内分布排泄速度较快,肺组织浓度最高,蛋白结合率高,主要通过胆汁排泄。应用于临床时,需综合考虑各种因素对     

Discovery and development of heat shock protein 90 inhibitors as anticancer agents: a review of patented potent geldanamycin derivatives

Introduction: There has been research on anticancer strategies which focus on disrupting a single malignant protein. One of the strategies is the inhibition of one protein, heat shock protein 90 (Hsp90). There are many reasons why Hsp90 protein is targeted by anticancer agents: maintenance of cellular homeostasis in organisms involves Hsp90 and its client proteins; moreover, Hsp90 complex is involved in regulating several signal transduction pathways and plays an important role in the maturation of lots of tumor-promoting client proteins. Geldanamycin (GM), the first benzoquinone ansamycin, has shown anticancer activity by binding to Hsp90. Currently, several GM derivatives such as 17-AAG, 17-(2-dimethylaminoethyl)amino-17-demethoxygeldanamycin, IPI-493, and IPI-504 are being progressively developed toward clinical application.

Areas covered: Several research groups have studied GM and its derivatives to develop novel and potent Hsp90 inhibitors for the treatment of cancer. The crystal structure of Hsp90 was utilized to undergo structural optimization of GM derivatives. A wide variety of structural modifications were performed and some of the derivatives are now in clinical studies. The aim of this review was to summarize and analyze the structure-activity relationships of GM derivatives and the focus is on patented novel and pharmaceutically efficacious derivatives published from 1971 to 2012.

Expert opinion: Hsp90 inhibitors offer an effective therapeutic approach for treatment of cancer. To date, the clinical results of 17-AAG, IPI-493, and IPI-504 suggest that these GM derivatives could be used either alone or in combination with other marketed medications for the treatment of cancer patients. As there are not any marketed Hsp90 inhibitors, inhibiting Hsp90 chaperone function remains as a promising strategy that still requires further research.     

Benzoquinone ansamycin 17AAG binds to mitochondrial voltage-dependent anion channel and inhibits cell invasion

Geldanamycin and its derivative 17AAG [17-(Allylamino)-17-demethoxygeldanamycin, telatinib] bind selectively to the Hsp90 chaperone protein and inhibit its function. We discovered that these drugs associate with mitochondria, specifically to the mitochondrial membrane voltage-dependent anion channel (VDAC) via a hydrophobic interaction that is independent of HSP90. In vitro, 17AAG functions as a Ca(2+) mitochondrial regulator similar to benzoquinone-ubiquinones like Ub0. All of these compounds increase intracellular Ca(2+) and diminish the plasma membrane cationic current, inhibiting urokinase activity and cell invasion. In contrast, the HSP90 inhibitor radicicol, lacking a bezoquinone moiety, has no measurable effect on cationic current and is less effective in influencing intercellular Ca(2+) concentration. We conclude that some of the effects of 17-AAG and other ansamycins are due to their effects on VDAC and that this may play a role in their clinical activity.