Recently, targeting metabolic reprogramming has emerged as a potential therapeutic approach for fighting cancer. Sterol regulatory element binding protein-2 (SREBP-2), a basic helix-loop-helix leucine zipper transcription factor, mainly regulates genes involved in cholesterol biosynthesis and homeostasis. SREBP-2 binds to the sterol regulatory elements (SREs) in the promoters of its target genes and activates the transcription of mevalonate pathway genes, such as HMG-CoA reductase (HMGCR), mevalonate kinase and other key enzymes. In this review, we first summarized the structure of SREBP-2 and its activation and regulation by multiple signaling pathways. We then found that SREBP-2 and its regulated enzymes, including HMGCR, FPPS, SQS, and DHCR4 from the mevalonate pathway, participate in the progression of various cancers, including prostate, breast, lung, and hepatocellular cancer, as potential targets. Importantly, preclinical and clinical research demonstrated that fatostatin, statins, and N-BPs targeting SREBP-2, HMGCR, and FPPS, respectively, alone or in combination with other drugs, have been used for the treatment of different cancers. This review summarizes new insights into the critical role of the SREBP-2-regulated mevalonate pathway for cancer and its potential for targeted cancer therapy.

/pdf/targeting-srebp-2-regulated-mevalonate-metabolism-for-cancer-2gr291abk1.pdf

Targeting SREBP-2-Regulated Mevalonate Metabolism for Cancer Therapy.

Prostate cancer (PCa) is the most diagnosed malignancy in the men worldwide. Cancer stem cells (CSCs) are the sub-population of cells present in the tumor which possess unique properties of self-renewal and multilineage differentiation thus thought to be major cause of therapy resistance, disease relapse, and mortality in several malignancies including PCa. CSCs have also been shown positive for the common stem cells markers such as ALDH EZH2, OCT4, SOX2, c-MYC, Nanog etc. Therefore, isolation and characterization of CSCs specific markers which may discriminate CSCs and normal stem cells are critical to selectively eliminate CSCs. Rapid advances in the field offers a theoretical explanation for many of the enduring uncertainties encompassing the etiology and an optimism for the identification of new stem-cell targets, development of reliable and efficient therapies in the future. The emerging reports have also provided unprecedented insights into CSCs plasticity, quiescence, renewal, and therapeutic response. In this review, we discuss the identification of PCa stem cells, their unique properties, stemness-driving pathways, new diagnostics, and therapeutic interventions. 

Cancer stem cell in prostate cancer progression, metastasis and therapy resistance.

Introduction: Bone metastases affect the majority of patients with castration-resistant prostate cancer (CRPC), resulting in significant morbidity and mortality. This review describes the current therapies available for the management of CRPC patients with bone metastases.Areas covered: Studies on the use of currently available therapeutic approaches for palliating pain, delaying skeletal-related events (SREs) and prolonging survival in CRPC patients with bone metastases have been examined. PubMed database was searched in May 2016 starting with the following keywords: (‘castration-resistant prostate cancer’ OR ‘CRPC’) AND ‘bone metastases’, and approximately 270 results were retrieved. More specific searches were then performed on the epidemiology and molecular pathogenesis (in particular, ‘vicious cycle’ was used as a keyword), the management of pain, SREs and survival. The following keywords were also used individually: abiraterone, cabazitaxel, denosumab, docetaxel, enzalutamide, radium-223, si...

Therapeutic management of bone metastasis in prostate cancer: an update

Zoledronic acid, a nitrogen‐containing bisphosphonate drug, is used for the treatment of osteoporosis, Paget's disease of bone, and tumor‐induced osteolysis. Zoledronic acid has also gained a place in cancer treatment due to its cytotoxic and antiproliferative effects in many cancer cells. Although zoledronic acid is considered safe, kidney damage is still one of the concerns in therapeutic doses. In the study, the aim was to assess the nephrotoxic profiles of zoledronic acid in the human embryonic kidney (HEK‐293) cells. Cytotoxicity evaluation was performed by 3‐[4,5‐dimethylthiazol‐2‐yl]−2,5‐diphenyl‐tetrazolium bromide (MTT) and neutral red uptake tests, while oxidative stress was performed by reactive oxygen species (ROS) production via flow cytometry, and the incomprehensible evaluation of ROS‐related genes by RT‐PCR and apoptosis was performed with Annexin‐PI analysis in flow cytometry. The obtained result showed that zoledronic acid inhibited cell viability (IC50 values were determined as 273.16  by MTT) and cell proliferation in a concentration‐dependent manner, induced ROS production, caused glutathione depletion, and increased oxidative stress index and endoplasmic reticulum (ER) stress, indicating severe cellular stress. The expression levels of oxidative damage (L‐fabp, α‐GST, Nrf2, and HMOX1), ER stress (CASP4, IRE1‐α, GADD153, and GRP78), and apoptosis (Bcl‐2, Bax, Cyt‐c, p53, CASP9, CASP3, NF‐κB, TNF‐α, and JNK) related genes were altered as well as IRE1‐α protein levels. Herein, we were the first to show that increased oxidative stress and ER stress resulting in apoptosis are the key molecular pathways in zoledronic acid‐induced nephrotoxicity equivalent to clinically administered concentrations.

Zoledronic acid‐induced oxidative damage and endoplasmic reticulum stress‐mediated apoptosis in human embryonic kidney (HEK‐293) cells

Prostate cancer (PC) preserves its leading position among male tumors. Ductal carcinoma is the second common type of prostate adenocarcinoma. The paper describes different types of ductal carcinoma, which have their morphological pattern. Ductal adenocarcinoma is a relatively rare morphological type of prostate adenocarcinoma traditionally regarded as a more aggressive type of PC, which is represented by the common forms with high Gleason scores (9, 10) and no well-defined treatment regimen. This paper describes 3 cases of ductal PC diagnosed at our center.

/pdf/protokovyi-rak-predstatelnoi-zhelezy-35ctef1979.pdf

Протоковый рак предстательной железы

Skeletal-related events (SREs), common sequelae of metastatic cancer, are reduced by bisphosphonates. In this study, it was postulated that radiopharmaceuticals, added to bisphosphonates, could further decrease the incidence of SREs. NRG Oncology RTOG 0517 randomized patients with breast, lung, and prostate cancer and blastic bone metastases to either zoledronic acid (ZA) alone or ZA plus radiopharmaceuticals (Sr-89 or Sm-153). The primary endpoint was time to development of SREs. Secondary objectives included quality of life (QOL), pain control, overall survival (OS), and toxicity. 261 patients (median age 68; 62% male; 55% prostate, 35% breast, 10% lung) were accrued between July 2006 and February 2011. The study closed early due to a lower than expected rate of SREs. 52 (42%) patients in the ZA arm and 49 (40%) in the radiopharmaceutical arm experienced an SRE. Median time free of SREs was 29.9 and 27.4 months, respectively (p = 0.84). Median OS in the ZA arm and radiopharmaceutical arms was 32.1 and 26.9 months, respectively (p = 0.37). Cox proportional hazards regression model showed that primary disease site (lung) and number of bone metastases (> 2) had a negative impact on OS (p < 0.0001, p = 0.01, respectively). The addition of radiopharmaceuticals to ZA led to a significant reduction in pain at 1 month based on BPI worst score (p = 0.02). No other group differences were noted for QOL or toxicity. The addition of radiopharmaceuticals to bisphosphonates did not alter time to SREs or OS for patients with breast, lung, prostate cancers and blastic bone metastases, although it was associated with significant pain reduction at 1 month. This protocol (RTOG 0517) is registered with ClinicalTrials.gov (NCT00365105), and may be viewed online at http://www.clinicaltrials.gov/ct2/show/NCT00365105?term=RTOG+0517&rank=1
 .

/pdf/randomized-phase-iii-trial-to-evaluate-radiopharmaceuticals-4jzqutnhn9.pdf

Randomized phase III trial to evaluate radiopharmaceuticals and zoledronic acid in the palliation of osteoblastic metastases from lung, breast, and prostate cancer: report of the NRG Oncology RTOG 0517 trial

TPS9150 Background: Skeletal related events (SREs) diminish quality of life (QOL) as well as overall survival (OS) in patients with bone metastases, a common event in breast, lung and prostate canc...

Randomized phase III trial to evaluate radiopharmaceuticals and zoledronic acid in the palliation of osteoblastic metastases from lung, breast, and prostate cancer: Report of RTOG 0517.

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Randomized phase III trial to evaluate radiopharmaceuticals and zoledronic acid in the palliation of osteoblastic metastases from lung, breast, and prostate cancer: report of the NRG Oncology RTOG 0517 trial

Randomized phase III trial to evaluate radiopharmaceuticals and zoledronic acid in the palliation of osteoblastic metastases from lung, breast, and prostate cancer: Report of RTOG 0517.