The role of heat shock proteins in cancer.

Mitochondria play a key role in ATP generation, redox homeostasis and regulation of apoptosis. Due to the essential role of mitochondria in metabolism and cell survival, targeting mitochondria in cancer cells is considered as an attractive therapeutic strategy. However, metabolic flexibility in cancer cells may enable the upregulation of compensatory pathways, such as glycolysis to support cancer cell survival when mitochondrial metabolism is inhibited. Thus, compounds capable of both targeting mitochondria and inhibiting glycolysis may be particularly useful to overcome such drug-resistant mechanism. This review provides an update on recent development in the field of targeting mitochondria and novel compounds that impact mitochondria, glycolysis or both. Key challenges in this research area and potential solutions are also discussed.

Targeting cancer cell mitochondria as a therapeutic approach: recent updates.

The discovery and identification of the human epidermal growth factor receptor 2 (HER’s-2) genes, have led to a better understanding of breast tumour biology. A member of the epidermal growth factor receptor family, it is a potent mediator of cellular growth and proliferation in malignant epithelial cells. Amplification or over expression of HER-2 occurs in approximately 15–30 % of breast cancers and 10–30 % of gastric/gastroesophageal cancers and serves as a prognostic and predictive biomarker. Treatment with HER-2 targeted monoclonal antibody, trastuzumab dramatically improved outcome in patients with breast malignancy. This promising approach led to the development of pertuzumab, ado-trastuzumab emtansine and lapatinib. The development of drug resistance and disease progression due to alternate signalling remained a real therapeutic challenge. Several research studies are currently focused on inhibition of onco-proteins, kinases and growth factors linked to HER-2 positive breast cancers. The success of immune checkpoint modulators and vaccines in preliminary studies describes the role of tumour immunity. Apart from its role in the pathogenesis of various cancers, HER-2 directed therapeutic approach has brought about a revolutionary change in terms of time to progression and survival rates in breast cancers. Keywords: ErbB-2 signalling, Targeted approach, Trastuzumab, Drug resistance

Her-2 gene, receptors and drug target: a systematic review

As a heat shock protein 90 inhibitor, 17-allylamino-17‑demethoxygeldanamycin (17-AAG) has been studied in numerous types of cancer, however the effects of 17-AAG on apoptosis and the cell cycle of H446 cells remain unclear. In the current study, the MTT method was used to evaluate the inhibitory effects of different durations and doses of 17‑AAG treatment on the proliferation of H446 cells. The cells were stained with Annexin-fluorescein isothiocyanate/propidium iodide and measured by flow cytometry, and the gene and protein expression levels of signal transducer and activator of transcription 3 (STAT3), survivin, cyclin D1, cyt‑C, caspase 9 and caspase 3 were determined by reverse transcription‑quantitative polymerase chain reaction and western blot analysis. The results indicated that with treatment with 1.25‑20 mg/l 17‑AAG for 24 and 48 h, significant inhibition of H446 cell proliferation was observed in a time‑ and dose‑dependent manner. With treatment of 3.125, 6.25 and 12.5 mg/l 17‑AAG for 48 h, significant apoptosis and cell cycle arrest was observed. The results indicated that the gene and protein expression levels of STAT3, survivin and cyclin D1 were downregulated, and cyt‑C, caspase 9 and caspase 3 were upregulated by 17‑AAG in a dose-dependent manner when the cells were treated with 3.125 and 6.25 mg/l 17-AAG for 48 h. The results indicated that 17‑AAG is able to inhibit the cell proliferation, induce apoptosis and G2/M arrest and downregulate the gene and protein expression levels of STAT3, survivin and cyclin D1, and upregulate gene and protein expression of cyt‑C, caspase 9, caspase 3.

/pdf/effects-of-17-aag-on-the-cell-cycle-and-apoptosis-of-h446-3a4reqta8f.pdf

Effects of 17-AAG on the cell cycle and apoptosis of H446 cells and the associated mechanisms.

Fil: Ciocca, Daniel Ramon. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Conicet - Mendoza. Instituto de Medicina y Biologia Experimental de Cuyo; Argentina

Molecular Approaches to Target Heat Shock Proteins for Cancer Treatment

Since the early 2000s, there has been renewed interest in the development of Hsp90 inhibitors in oncology, with more than 15 compounds currently under evaluation in clinical trials. Because of Hsp90’s important role as a key molecular chaperone and its extensive list of oncogenic client proteins, there is sound biologic rationale in targeting it in anticancer therapy.

The early-generation Hsp90 inhibitors (geldanamycin, tanespimycin, alvespimycin) were unsuccessful because of limited efficacy, poor solubility, and dose-limiting toxicities including hepatotoxicity, but the second-generation agents—including retaspimycin, ganetespib, and NVP-AUY922—have shown some promising clinical activity that merits further clinical investigation. Although Hsp90 inhibitors are not currently ready for prime time, their role in targeting molecular subsets in solid tumours appears to hold the greatest promise, either as monotherapy or combination therapy for egfr- or alk-positive nsclc, chemosensitive nsclc adenocarcinoma, and possibly other yet-to-be-unidentified subtypes. The clinical relevance of Hsp90 inhibition in her2-positive metastatic breast cancer is, however, less clear, given the advent of novel agents such as pertuzumab and T-DM1, which have demonstrated robust activity in the trastuzumab-refractory population. It would certainly be of value to determine whether Hsp90 inhibitors retain activity after progression on multiple lines of anti-her2 therapies. Nonetheless, the triple-negative arm of the phase ii enchant-1 breast cancer trial evaluating ganetespib monotherapy has completed enrollment, and results are awaited with interest.

Moving forward, the question of whether off-target toxicities can be successfully minimized while clinical efficacy is achieved remains open, and the answer will ultimately determine the fate and success of Hsp90 inhibitors in clinic.

/pdf/hsp90-inhibitors-in-oncology-ready-for-prime-time-3jmq7gxtx3.pdf

Hsp90 inhibitors in oncology: ready for prime time?

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Hsp90 inhibitors in oncology: ready for prime time?