B5H7, a Morpholine Derivative of 23-Hydroxybetulinic Acid, Reverses Doxorubicin Resistance in HepG2/ADM
Pages 59-66
Nan Yao, Dao-Lu Liu, Ying-Jie Li, Zhe-Sheng Chen, Zhi Shi, Wei-Min Chen, Zhe Yao, Dong-Mei Zhang and Wen-Cai Ye

DOI: http://dx.doi.org/10.6000/1929-2279.2014.03.01.6

Published: 31 January 2014

Abstract: Multidrug resistance (MDR) is the major cause of the failure of cancer chemotherapy. Development of MDR reversers is an important strategy to improve the efficacy of cancer chemotherapy. Here, we have found a morpholine derivative of 23-hydroxybetulinic acid, B5H7, with a reversal effect on MDR cancer cells. Our studies showed that B5H7 enhanced cytotoxicity of doxorubicin, but no cisplatin in MDR cancer cells HepG2/ADM. And we found that B5H7 not only increased the intracellular accumulation of P-glycoprotein substrates doxorubicin and rhodamine123, but also reduced the efflux of rhodamine123 in HepG2/ADM cells. Further studies showed B5H7 did not alter the protein level of P-glycoprotein and it also had no effect on P-glycoprotein ATPase activity. Taken together, we have found that B5H7 could reverse doxorubicin resistance in HepG2/ADM cells by inhibiting the transport function of P-glycoprotein. These findings contribute to developing B5H7 as an adjuvant to anticancer chemotherapy with doxorubicin.

Multiple Mechanisms for Anti-Fibrotic Functions of Statins on Radiotherapy Induced Fibrosis
Pages 67-72
Chao Li, Wei Li, Lathika Mohanraj, Qing Cai, Mitchell S. Anscher and Youngman Oh

DOI: http://dx.doi.org/10.6000/1929-2279.2014.03.01.8

Published: 31 January 2014

Abstract: Radiotherapy-induced fibrosis (RTIF)presents a challenge in radiotherapy for cancer patients. Although numerous studies have attempted to elucidate the mechanisms leading to RTIF, the pathogenesis of RTIF at the cellular and molecular level is still incompletely described. One key component involved in the post-radiation injury is the pleuripotent cytokine transforming growth factor (TGF)-β. TGF-β signaling pathway has been under intensive investigation about its critical role in radiation-induced fibroproliferative disease. Connective tissue growth factor (CTGF), also known as insulin-like growth factor binding protein-related protein 2 (IGFBP-rP2) is a potent regulator of fibroblast proliferation, cell adhesion, andstimulation of extracellular matrix production. CTGF is known as a major downstream mediator of the chronic fibrotic effects of TGF-β. Here we have demonstrated that irradiation and TGF-β induced CTGF, subsequently upregulates fibrotic factors such as fibronectin and type IV collagen. Furthermore, as HMG-CoA reductase inhibitors, statins inhibit expressions of CTGF and downstream fibrotic proteins in both normal human fetal fibroblasts (HFL-1) and human dermal fibroblasts (HDF) on TGF-β treatment or irradiation. Our study also demonstrates that simvastatin not only suppressed TGF-β-induced fibrosis through inhibition of CTGF production but also CTGF-induced fibrosis. We further show that simvastatin may act in a TGF-β-independent manner by inhibiting Rho kinase pathway. Taken together, these data suggest that radiotherapy may upregulate CTGF expression in a TGF-β-dependent and -independent manner, thereby enhancing expression of profibrotic factors and inducing lung fibrosis.

The Oncological Outcome of HIFU for the Treatment of Localized Prostate Cancer
Pages 67-72
Francesco Ziglioli and Umberto Maestroni

DOI: http://dx.doi.org/10.6000/1929-2279.2014.03.01.7

Published: 31 January 2014

Abstract: Introduction: Prostate cancer is considered one of the most important health problems. Due to the increased number of diagnosed patients and the inability to distinguish aggressive tumors, minimally-invasive procedures have become increasingly interesting. High-intensity focused ultrasound (HIFU) is an alternative option to radical surgery to treat prostate cancer. To date, however, no data are available on the efficacy of this technique in comparison to standard treatment.

Methods and Results: We reviewed the literature to concentrate on the oncological outcome of HIFU treatment of prostate cancer with the following key words: hifu, high intensity focused ultrasound, ultrasonic therapy, transrectal hifu, prostate ablation. MedLine and Embase via Ovid database were searched. Selection criteria were: English language, articles published between 2006 and 2013, case series including more than 150 participants and reported data on oncological outcome. Thirteen uncontrolled studies were identified. No randomized controlled trials (RCT) were found in the literature comparing HIFU to other routine approaches to prostate cancer treatment.

Conclusion: HIFU seems to be a promising minimally-invasive treatment for low- and intermediate-risk prostate cancer, especially for patients who are unfit for radical surgery. Prospective studies with longer follow-up periods and RCT are required to properly assess the benefits of HIFU and to compare this treatment with standard treatment.

Vascular Disease and Prostate Cancer: A Conflicting Association
Pages 81-84
Simona Di Francesco¹ and Raffaele L. Tenaglia²

DOI: http://dx.doi.org/10.6000/1929-2279.2014.03.01.9

Published: 31 January 2014

Abstract: Background: To date, only a few studies have explored the relationship between vascular disease and Prostate Cancer (PCa), with conflicting results. The Aim of the research was to investigate the association of carotid vascular disease (CVD) or Coronary Artery disease (CAD) with PCa hormone-naïve at initial diagnosis.

Methods: Retrospective analysis of 266 patients undergoing prostate biopsy at our institution between 2006 and 2009 was conducted. We examined associations of CVD or CAD in 133 patients with PCa diagnosis versus 133 age-matched controls. Men with incomplete data available, history of hormone therapy or chemotherapy, prostate or bladder surgery were excluded.

Results:CVD was significantly linked to PCa in all cases versus controls at initial diagnosis of PCa (OR 2.42, p < 0.05). Similarly CAD was significantly related to PCa at initial diagnosis (OR 1.88, p < 0.05).

Conclusions: In our study a significant relation was found between vascular damage and PCa hormone-naïve at initial diagnosis. Further research should elucidate these associations in larger samples to confirm these relationships and to stabilize future prevention strategies.