Abstract
ATP-binding cassette subfamily G member 2 (ABCG2) is a member of the ABC transporter superfamily proteins, which has been implicated in the development of multidrug resistance (MDR) in cancer, apart from its physiological role to remove toxic substances out of the cells. The diverse range of substrates of ABCG2 includes many antineoplastic agents such as topotecan, doxorubicin and mitoxantrone. ABCG2 expression has been reported to be significantly increased in some solid tumors and hematologic malignancies, correlated to poor clinical outcomes. In addition, ABCG2 expression is a distinguishing feature of cancer stem cells, whereby this membrane transporter facilitates resistance to the chemotherapeutic drugs. To enhance the chemosensitivity of cancer cells, attention has been focused on MDR modulators. In this study, we investigated the effect of a tetrodotoxin-resistant sodium channel blocker, A-803467 on ABCG2-overexpressing drug selected and transfected cell lines. We found that at non-toxic concentrations, A-803467 could significantly increase the cellular sensitivity to ABCG2 substrates in drug-resistant cells overexpressing either wild-type or mutant ABCG2. Mechanistic studies demonstrated that A-803467 (7.5 μM) significantly increased the intracellular accumulation of [(3)H]-mitoxantrone by inhibiting the transport activity of ABCG2, without altering its expression levels. In addition, A-803467 stimulated the ATPase activity in membranes overexpressed with ABCG2. In a murine model system, combination treatment of A-803467 (35 mg/kg) and topotecan (3 mg/kg) significantly inhibited the tumor growth in mice xenografted with ABCG2-overexpressing cancer cells. Our findings indicate that a combination of A-803467 and ABCG2 substrates may potentially be a novel therapeutic treatment in ABCG2-positive drug resistant cancers.
Highlights
Multidrug resistance (MDR) is defined as the resistance of cancer cells to antineoplastic agents that have distinct structures and mechanisms of action [1]
HEK293 cells transfected with wild-type (HEK293/R482) and mutant (HEK293/ R482G and HEK293/R482T) ATP-binding cassette subfamily G member 2 (ABCG2) (Supplementary Figure S2) showed significant resistance to MX and topotecan compared to HEK293/pcDNA3.1 (Table 1)
We found similar results where A-803467 significantly increased the cytotoxicity of MX and topotecan in ABCG2 overexpressing H460/MX20 cells (Table 2)
Summary
Multidrug resistance (MDR) is defined as the resistance of cancer cells to antineoplastic agents that have distinct structures and mechanisms of action [1]. The potential mechanisms of MDR include pharmacokinetic alterations, tumor micro-environmental changes, or cancer cell-specific factors that occur at different levels due to cellular alterations, which include increased drug efflux or decreased drug uptake, drug inactivation, drug target modification or apoptosis evasion [4]. The ATPbinding cassette (ABC) multidrug transporters such as ABCB1 (MDR1/P-glycoprotein), ABCC1 (MRP1) and ABCG2 (BCRP/MXR) are considered to be accountable for the majority of drug efflux in human cancers [5]. Increased ABCG2 gene expression has been related to poor response to chemotherapy in childhood acute myeloid leukemia (AML) and relapsed AML [10, 11]. ABCG2 expression has been reported in various solid tumors, such as those present in the digestive tract, endometrium and melanoma [14]
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