Does HMGB1 gene silence really attenuate doxorubicin's cardiotoxicity?

GUVEN, Eylem TASKIN; GUVEN, Celal; SARIMAN, Melda; EMRENCE, Zeliha; EKMEKCI, Sema Sirma; ABACI, Neslihan; SEVGILER, Yusuf; SAHIN, Leyla; KOCAHAN, Sayad; AKCAKAYA, Handan

Doxorubicin (DOX) is one of the drugs for using cancer therapy, exceptionally solid and leukemia. However, its clinical utility is limited due to the drug toxicity on noncancerous tissue such as heart, liver, kidney, testis, etc. It is well known that the most adverse effect it's is seen on heart tissue. It is not still completely understood the mechanism of DOX-induced heart failure. High mobility group box 1 (HMGB1) is a chromatin protein highly conservative among the species. HMGB1 has a connection between cell's survival and death pathways. Until now, there has been no significant report refers the interaction between DOX and HMGB1 and AMP-activated kinase (AMPK) in the same experimental study. So, the study aimed to investigate whether DOX-induced heart failure mediates HMGB1 to initiate the apoptosis through (AMPK-α1) by TLR4 or not. In the study, H9c2 cell line has used the study. It was created four groups as a control, HMGB1 inhibition, DOX, DOX+HMGB1 inhibition. Silencing HMGB1 was performed with specific small interfering RNA (siRNA, 10 nM). DOX was used at two μM concentration for 36 and 48 hours. Protein and genes expressions, apoptosis was measured. Although DOX gave rise to decrease AMPK, P-AMPK, ERK1/2, PERK1/2, P38, JNK protein expression, DOX+HMGB1 inhibition led to change those protein expressions. The number of TUNEL positive and active caspase eight cells at DOX was high, although HMGB1 silencing could heal the cell numbers. HMGB1 plays an essential role as amplifying on DOX toxicity on the heart by TLR4. This study was financially supported by TUBITAK (114S118).

DOXORUBICIN; CARDIOTOXICITY; ATRIAL fibrillation; CLINICAL trials; CANCER treatment

Journal of Cellular Neuroscience & Oxidative Stress, 2018, Vol 10, Issue 2, p704

2149-7222

Academic Journal