Lobaplatin promotes 125I-induced apoptosis and inhibition of proliferation in hepatocellular carcinoma by upregulating PERK-eIF2α-ATF4-CHOP pathway

Abstract

We investigated the mechanism underlying the effect of a combination treatment of 125I radioactive seed implantation and lobaplatin (LBP) in hepatocellular carcinoma. The effects of administration of HCC cells and subcutaneous tumor model of mice with different doses of 125I or a sensitizing concentration of LBP alone, or in combination, on cellular apoptosis and proliferation were analyzed and it was confirmed that LBP promotes 125I-induced apoptosis and inhibition of proliferation of HCC. Furthermore, isobaric tag for relative and absolute quantification labeling analyses suggested that 125I promoted the apoptosis and inhibition of proliferation of HCC cells by upregulating the expression of PERK-eIF2α-ATF4-CHOP pathway, a well-known apoptosis-related pathway. Moreover, LBP was found to boost the 125I-induced upregulation of this pathway and increase the apoptosis. Our data indicate that LBP promotes the apoptotic and anti-proliferative effects of 125I and provide a firm foundation for better clinical application of this combination therapy.

Lobaplatin Enhances Radioactive 125I Seed-Induced Apoptosis and Anti-Proliferative Effect in Non-Small Cell Lung Cancer by Suppressing the AKT/mTOR Pathway

“…From our previous study, we saw that 125 I could induce cellular apoptosis and cell cycle arrest in PANC-1 cells; 21 moreover, another recent study on HCC demonstrated that LBP promoted 125 I-induced apoptosis and anti-proliferative effect via the PERK-eIF2α-ATF4-CHOP pathway, which we identified by iTraq. 20 In our present study, we verified that 125 I could significantly inhibit tumor growth in vivo and decrease proliferation with G2/M cell cycle arrest in vitro; interestingly, these anticancer effects could be enhanced by LBP.…”

“…Our previous research indicated that 125 I induced apoptosis and proliferation inhibition in HCC by upregulating the PERK-eIF2α-ATF4-CHOP pathway. 20 Based on our previous iTraq results, we found that the function of 125 I is related to the AKT/mTOR pathway. In this study, we explored whether LBP could sensitize A549 cells to 125 I radiation and determined the potential links among 125 I, LBP, and the AKT/mTOR pathway.…”

“…LBP has been reported as the first-line treatment for NSCLC with minimal side effects and high specificity. 9,20,22 Moreover, combining LBP with radiotherapy resulted in a better clinical efficacy than did single treatment alone. 7 However, drug resistance is an important factor that affects LBP clinical efficacy.…”

“…The mouse tumor model was established following the method we previously described. 20 A549 cells (1×10 7 / mL) were diluted in 0.9% saline solution and injected subcutaneously in the hind leg of BALB/c male nude mice (n=16, 4-6 weeks) purchased from the Animal Research Center of Shandong University (Jinan, Shandong, China). Tumor diameter was measured every other day.…”

“…According to the previously published method, 10% of the IC 50 was considered as a sensitizing concentration. 20…”