3alpha-Hydroxytanshinone IIA

Sodium Tanshinone IIA Sulfonate Prevents Radiation-Induced Toxicity in H9c2 Cardiomyocytes.[Pubmed:28386289]

Evid Based Complement Alternat Med. 2017;2017:4537974.

The present study was designed to elucidate the key parameters associated with X-ray radiation induced oxidative stress and the effects of STS on X-ray-induced toxicity in H9c2 cardiomyocytes. Cytotoxicity of STS and radiation was assessed by MTT. Antioxidant activity was evaluated by SOD and MDA. Apoptosis was measured by the flow cytometry, Hoechst 33258, clonogenic survival assay, and western blot. It was found that the cell viability of H9c2 cells exposed to X-ray radiation was significantly decreased in a dose-dependent manner and was associated with cell cycle arrest at the G0/G1 phase as well as apoptosis. STS treatment significantly reversed the morphological changes, attenuated radiation-induced apoptosis, and improved the antioxidant activity in the H9c2 cells. STS significantly increased the Bcl-2 and Bcl-2/Bax levels and decreased the Bax and caspase-3 levels, compared with the cells treated with radiation alone. STS treatment also resulted in a significant increase in p38-MAPK activation. STS could protect the cells from X-ray-induced cell cycle arrest, oxidative stress, and apoptosis. Therefore, we suggest the STS could be useful for the treatment of radiation-induced cardiovascular injury.

Fludarabine resistance mediated by aminoglycoside-3'-phosphotransferase-IIa and the structurally related eukaryotic cAMP-dependent protein kinase.[Pubmed:28373209]

FASEB J. 2017 Jul;31(7):3007-3017.

While working with G418-resistant stably transfected cells, we realized the neomycin resistance (NeoR) gene, which encodes the aminoglycoside-3'-phosphotransferase-IIa [APH(3')-IIa], also confers resistance to the nucleoside analog fludarabine. Fludarabine is a cytostatic drug widely used in the treatment of hematologic and solid tumors, as well as in the conditioning of patients before transplantation of hematopoietic progenitors. We present evidence that NeoR-transfected cells do not incorporate fludarabine, thus avoiding DNA damage caused by the drug, evidenced by a lack of FANCD2 monoubiquitination and impaired apoptosis. A screening of other nucleoside analogs revealed that APH(3')-IIa only protects against ATP purine analogs. Moreover, APH(3')-IIa ATPase activity is inhibited by fludarabine monophosphate, suggesting that APH(3')-IIa blocks fludarabine incorporation into DNA by dephosphorylating its active fludarabine triphosphate form. Furthermore, overexpression of the catalytic subunit of the eukaryotic kinase PKA, which is structurally related to APHs, also provides resistance to fludarabine, anticipating its putative utility as a response marker to the drug. Our results preclude the use of Neo marker plasmids in the study of purine analogs and unveils a new resistance mechanism against these chemotherapeuticals.-Sanchez-Carrera, D., Bravo-Navas, S., Cabezon, E., Arechaga, I., Cabezas, M., Yanez, L., Pipaon, C. Fludarabine resistance mediated by aminoglycoside-3'-phosphotransferase-IIa and the structurally related eukaryotic cAMP-dependent protein kinase.

The MOBILE Study-A Phase IIa Enriched Enrollment Randomized Withdrawal Trial to Assess the Analgesic Efficacy and Safety of ASP8477, a Fatty Acid Amide Hydrolase Inhibitor, in Patients with Peripheral Neuropathic Pain.[Pubmed:28383710]

Pain Med. 2017 Dec 1;18(12):2388-2400.

Objective: To evaluate the analgesic efficacy and safety of ASP8477 in patients with peripheral neuropathic pain (PNP). Design: Enriched enrollment randomized withdrawal. Setting: Centers in Poland (four), Czech Republic (six), and the United Kingdom (two). Subjects: Patients aged 18 years or older with PNP resulting from painful diabetic peripheral neuropathy or postherpetic neuralgia. Methods: A four-week screening period followed by a single-blind period (six-day dose titration and three-week maintenance period with ASP8477 [20/30 mg BID]). Treatment responders (defined as a >/=30% decrease in the mean average daily pain intensity during the last three days of the single-blind period) were stratified by disease and randomized to receive placebo or continue ASP8477 during a three-week, double-blind, randomized withdrawal period. The primary end point was change in mean 24-hour average numeric pain rating scale (NPRS) from baseline to end of double-blind period. Results: Among 132 patients who enrolled, 116 entered the single-blind period and 63 (ASP8477, N = 31; placebo, N = 32) completed the double-blind period. There was no difference in mean 24-hour average NPRS score (P = 0.644) or in time-to-treatment failure (P = 0.485) between ASP8477 and placebo. During the single-blind period, 57.8% of patients were treatment responders. ASP8477 was well tolerated. During the single-blind period, 22% of patients experienced at least one treatment-related adverse event (TEAE); during the double-blind period, 8% in the ASP8477 arm and 18% in the placebo arm experienced at least one TEAE. Conclusions: ASP8477 was well tolerated in patients with PNP; however, ASP8477 did not demonstrate a significant treatment difference compared with placebo.

Randomized study between radical surgery and radiotherapy for the treatment of stage IB-IIA cervical cancer: 20-year update.[Pubmed:28382797]

J Gynecol Oncol. 2017 May;28(3):e34.

OBJECTIVE: Stage IB-IIA cervical carcinoma can be equally cured either by radical surgery or radiotherapy (RT). Albeit such policies show the same efficacy, they carry a different morbidity. This is an update after 20 years of a previously published randomized trial of RT vs. surgery in the treatment of stage IB-IIA cervical cancers to assess long-term survival and morbidity and the different pattern of relapse between the 2 modalities. METHODS: Between September 1986 and December 1991, women referred for a newly diagnosed stage IB and IIA cervical carcinoma were randomized to radical surgery or RT. The primary outcome measures were long-term survival and complications rate. The secondary outcome was recurrence of the disease. RESULTS: Three-hundred forty-three eligible women were randomized: 172 to radical surgery and 171 to external RT. Minimum follow-up was 19 years. Thirty-three patients (10%) died of intercurrent disease (31 cases) or fatal complications (2 cases). Twenty-year overall survival is 72% and 77% in the 2 treatment groups (p=0.280), respectively. As a whole, 94 recurrences (28%) were observed. Median time to relapse was 13.5 (surgery group) and 11.5 months (radiotherapy group) (p=0.100), respectively. Multivariate analysis confirms that risk factors for survival are histotype (p=0.020), tumor diameter (p=0.008), and lymph node status (p<0.001). CONCLUSION: The results of the present study seem to suggest that there is no treatment of choice for early stage cervical carcinoma in terms of survival. Long term follow-up confirms that the best treatment for the individual patient should take into account clinical factors such as menopausal status, comorbidities, histological type, and tumor diameter.