Introduction

ATL, a highly aggressive non-Hodgkin lymphoma that is usually accompanied by visceral involvement, is a peripheral T cell neoplasm associated with Human T cell leukemia virus type 1 (HTLV-1), a type C oncoretrovirus (Tsukasaki and Tobinai, 2012; Hermine et al., 2018). HTLV-1 oncoprotein Tax interacts with intracellular signaling pathways and modulates transcription of cellular genes involved in cell cycle progression, cell proliferation, and apoptosis resulting in immortalization and transformation of HTLV-1 infected cells and ATL pathogenesis (Tanaka et al., 1990; Ressler et al., 1997; Mulloy et al., 1998; Schmitt et al., 1998; Kashanchi and Brady, 2005; Matsuoka and Jeang, 2007; Zhang et al., 2017). In HTLV-1 infected cells, NF-κB is constitutively activated through Tax-dependent or –independent mechanisms and plays an important role in HTLV-1 oncogenesis and survival of HTLV-1 transformed T cells (Mori et al., 1999; Hironaka et al., 2004; Horie, 2007). Tax also contributes to the immortalization of HTLV-1 infected cells by transactivation of the c-MYC gene through the NF-κB pathway (Duyao et al., 1992). The interaction between c-MYC and the HTLV-1 latency maintenance factor p30Ⅱ enhances virus replication and oncogenesis (Romeo et al., 2015). About 30% of patients with ATL carry p53 mutations (Portis et al., 2001). Tax inhibits p53 transcriptional function in infected cells, thereby leading to the progression of ATL (Ariumi et al., 2000; Zane et al., 2012). Tax also interacts with inhibitors of CDK4 activity, leading to activation of CDK4 and dysregulated G1/S progression of the cell cycle (Suzuki et al., 1996; Haller et al., 2000; Yoshida, 2001). Tax expressing HTLV-1 infected T cells also express a high level of c-FLIPL and c-FLIPS which are potent death receptor inhibitory proteins known as tumor progression factors and act as antiapoptotic proteins by inhibiting death receptor-mediated apoptosis (Djerbi et al., 1999; Krueger et al., 2006). These alterations may together result in the leukemogenesis of HTLV-1 infected cells and ATL development.
Although several therapeutic approaches targeting different cellular pathways involved in cell cycle progression and cell proliferation have been applied for ATL therapy, treatment of ATL continues to be a significant challenge. Currently, no standard treatment exists for patients with ATL and long term efficacy of current treatments is limited. ATL is still an aggressive and intractable disease that carries a poor prognosis because of chemo-resistance and immunosuppression which increases vulnerability to opportunistic infections (Kchour et al., 2013). Multidrug resistance represents a major obstacle to the effective treatment of ATL. Resistance to chemotherapy may be correlated with the presence of Multidrug resistance (MDR) proteins (Yasunami et al., 2007).
Treating HTLV-1 infected cells with arsenic trioxide (ATO) revealed that ATO has therapeutic potential for ATL treatment by inhibiting the proliferation of HTLV-1 infected T cells and inducing apoptotic cell death (Ishitsuka et al., 1998; Mahieux et al., 2001; Ishitsuka et al., 2002). Combination therapy with ATO for HTLV-1 infection, triggers degradation of tax oncoprotein and consequently inactivates NF-κB signaling pathway, and induces cell death via cell cycle arrest and apoptosis induction (Bazarbachi et al., 1999; El-Sabban et al., 2000). Recently, herbal medicines in combinations with anticancer agents have been found to have cancer preventative and therapeutic activities (Wang et al., 2012; Arslan et al., 2013). Galbanic acid (GBA), a sesquiterpene coumarin compound isolated from Ferula species, has been reported to have noticeable anti-tumor and anti-viral activities and can counteract cancer through apoptosis induction, P-gp inhibition, and anti-angiogenesis and anti-proliferative activities (Bedniak et al., 1967; Iranshahi et al., 2007; Hanafi-Bojd et al., 2011; Iranshahy and Iranshahi, 2011; Kim et al., 2011; Kasaian et al., 2014). To date, no studies have investigated the effects of GBA in ATL. Thus, the present study was designed to determine whether GBA in combination with ATO would improve the therapeutic efficacy against ATL.