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Introduction
Multidrug drug resistance (MDR) is defined as concomitant existing resistance to several structurally and functionally diverse drugs (1–4). It is a very complicated and dynamical system composed of diverse cellular factors and signal transduction pathways. Major participants of MDR include drug transporter-mediated increased efflux of anticancer agents, evasion of drug-induced apoptosis and others (3,5). Most current chemotherapeutic drugs are substrates or inducers of drug transporters and induce cytotoxicity through apoptosis (1). Basing on this concept, recent research mainly focused on exploring and developing drugs reversing transport-mediated MDR and reactivating apoptosis. But most of these drugs failed to show clinical efficacy (6,7). Since MDR is modulated by a very complicated system, simply inhibiting one or two signal pathways or regulators can not succeed in overcoming it (1). Beside classical type of programmed cell death (apoptosis), other programmed death modalities exist, such as autophagy and programmed necrotic death (necroptosis) (8). Gradually increasing evidence demonstrates cancer cells resistant to current chemotherapeutic drugs are sensitive to drug-induced programmed necrotic death (9–11). Accordingly, contemporaneously activating multiple types of programmed cell death by multi-drug treatment regimen is a promising option to circumvent MDR, especially apoptosis tolerance.
Honokiol (HNK) is a small molecule isolated from Chinese traditional medicinal herb Houpu with various pharmacological activities. Among all its medicinal applications, antitumor activity is most extensively studied. Honokiol-induced apoptosis, including caspase-dependent and -independent apoptosis (12), is the most widely investigated and fundamental mechanism of its antitumor activity. Besides, other cell death forms, such as programmed necrotic cell death (9) and paraptosis (13), are also induced by honokiol at certain doses. Our group is devoted to mechanical research on antitumor effects of honokiol. Previous work of our group demonstrated that honokiol induced apoptosis in human colorectal carcinoma RKO cells associated with caspase cascade (14,15). Besides, we evaluated honokiol potentiated cytotoxic effect of adriamycin through downregulation of P-gycoprotein (P-gp) in drug resistant breast carcinoma cell line MCF-7/ADR (2). Further, our subsequent study first reported that honokiol induced a distinct programmed cell death modality, programmed necrotic death (9), initiating new insights and greatly expanding the cognition of its antitumor activity.
Most of the therapy studies concerning combination effect of two or more anticancer drugs only focus on ‘therapeutic synergy’. They lack quantitative data perhaps of composed...