Cisplatin sensitizes human hepatocellular carcinoma cells, but not hepatocytes and mesenchymal stem cells, to TRAIL within a therapeutic window partially depending on the upregulation of DR5

Abstract

Abstract. Tumor necrosis factor (TNF)-related apoptosisinducing ligand (TRAIL) is a member of the TNF family of cytokines and has been shown to induce cell apoptosis in many types of tumors, but not in normal cells. This tumorselective property has made TRAIL a promising approach for the development of cancer therapy. However, hepatocellular carcinoma (HCC) cells display a striking resistance to TRAIL. Although some chemotherapeutic agents can overcome this resistance, safety issues remain a concern because the combination of these agents and TRAIL has been reported to induce toxicity in normal hepatocytes. In this study, we examined whether cisplatin could reverse TRAIL resistance in HCC cells with different p53 status and evaluated the toxicity of combination TRAIL and cisplatin to normal hepatocytes and mesenchymal stem cells (MSCs). We observed that cisplatin could efficiently sensitize HCC cells, but not hepatocytes and MSCs to TRAIL-induced apoptosis within a wide therapeutic window. The apoptosis of HCC cells only partially depended on the upregulation of DR5 and the status of p53. In addition, we provide favorable evidence supporting the feasibility of the combination of chemotherapy and MSCs transduced with TRAIL.

Human mesenchymal stem cells lose their functional properties after paclitaxel treatment

“…As a more general phenomenon, it has been suggested that MSCs can escape apoptotic induction also after exposure to various other anti-cancer agents 27 , 30 , 34 . The observation of low apoptosis induction in MSCs has been attributed to an impaired p73-dependent activation of pro-apoptotic proteins, an inhibition of the TRAIL pro-apoptotic pathway and strong constitutive expression of several anti-apoptotic factors like Bcl-2 and Bcl-xL 35 – 37 . In our dataset, MSCs exhibited strong increases in senescence-associated β-galactosidase stainings even after low doses of paclitaxel; this may explain the observed inactivation of cellular proliferation in taxane-treated MSCs while preserving their metabolic viability.…”

Mesenchymal stem cells maintain their defining stem cell characteristics after treatment with cisplatin

“…This resistance against apoptotic activation has been reported after other forms of cytotoxic treatment 37 , and it has been suggested that the observed resistance of MSCs is due to a reduced p73-dependent activation of pro-apoptotic proteins, p21 and Bax and high constitutive expression levels of various anti-apoptotic proteins such as Bcl-2 and Bcl-xL 38 39 . Additionally, MSCs were shown to lack activation of the TRAIL pro-apoptotic pathway upon cisplatin treatment 40 .…”

A New Player in the Development of TRAIL Based Therapies for Hepatocarcinoma Treatment: ATM Kinase

“…Furthermore, these studies provide also the molecular mechanisms underlying the ability of these drugs to enhance TRAIL sensitivity (Table 2). In particular, cisplatin and 5-FU trigger the downregulation of the antiapoptotic proteins cFLIP and the upregulation of TRAIL - R1 and TRAIL-R2 receptors and may efficiently sensitize HCC cells, but not normal hepatocytes to TRAIL-induced apoptosis [28,60]. Conversely the synergistic effect of TRAIL and etoposide, does not rely on the increase of the expression of TRAIL receptors, but rather is associated with the amplification of the mitochondrial signal pathway [61].…”