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.