Key Points• RARa2 activates Wnt and hedgehog pathways in maintaining myeloma stem cell features and drug resistance.We previously demonstrated that RARa2 expression is increased in CD138 selected plasma cells of relapsed multiple myelomas (MMs), and increased expression was linked to poor prognosis in newly diagnosed MM patients. In the present study, we demonstrate that increased RARa2 confers myeloma stem cell features. Higher expression of RARa2 was identified in the multiple myeloma stem cell (MMSC) fraction. Overexpression of RARa2 in bulk MM cell lines resulted in: 1) increased drug resistance; 2) increased clonogenic potential; 3) activation of both Wnt and Hedgehog (Hh) pathways; 4) increased side population and aldehyde dehydrogenase levels; and 5) increased expression of embryonic stem cell genes. The opposite effects were seen with RARa2 knockdown. We demonstrate that RARa2 induces drug resistance by activating the drug efflux pump gene ABCC3 and anti-apoptotic Bcl-2 family members. Inhibition of Wnt signaling or ABCC3 function could overcome drug resistance in RARa2 overexpressing MM cells. We also showed that in the 5TGM1 mouse model, targeting of the Wnt and Hh pathways using CAY10404, cyclopamine, or itraconazole significantly reduced the myeloma tumor burden and increased survival. Targeting RARa2 or its downstream signaling pathways provides a potential strategy to eliminate

Chemotherapeutic drugs frequently encounter multidrug resistance. ATP from mitochondria helps overexpression of drug efflux pumps to induce multidrug resistance, so mitochondrial delivery as a means of "repurposing'' chemotherapeutic drugs currently used in the clinic appears to be a worthwhile strategy to pursue for the development of new anti-drug-resistant cancer agents. TPP-Pluronic F127-hyaluronic acid (HA) (TPH), with a mitochondria-targeting triphenylphosphine (TPP) head group, was first synthesized through ester bond formation. Paclitaxel (PTX)-loaded TPH (TPH/PTX) nanomicelles exhibited excellent physical properties and significantly inhibited A549/ADR cells. After TPH/ PTX nanomicelles entered acidic lysosomes through macropinocytosis, the positively charged TP/PTX nanomicelles that resulted from degradation of HA by hyaluronidase (HAase) in acidic lysosomes were exposed and completed lysosomal escape at 12 h, finally localizing to mitochondria over a period of 24 h in A549/ADR cells. Subsequently, TPH/PTX caused mitochondrial outer membrane permeabilization (MOMP) by inhibiting antiapoptotic Bcl-2, leading to cytochrome C release and activation of caspase-3 and caspase-9. In an A549/ADR xenograft tumor model and a drug-resistant breast cancer-bearing mouse model with lung metastasis, TPH/PTX nanomicelles exhibited obvious tumor targeting and significant antitumor efficacy. This work presents the potential of a single, nontoxic nanoparticle (NP) platform for mitochondria-targeted delivery of therapeutics for diverse drug-resistant cancers.

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BackgroundAloperine, a natural alkaloid constituent isolated from the herb Sophora alopecuroides displays anti-inflammatory properties in vitro and in vivo. Our group previously demonstrated that aloperine significantly induced apoptosis in colon cancer SW480 and HCT116 cells. However, its specific target(s) remain to be discovered in multiple myeloma (MM) and have not been investigated.MethodsHuman myeloma cell lines (n = 8), primary myeloma cells (n = 12), drug-resistant myeloma cell lines (n = 2), and animal models were tested for their sensitivity to aloperine in terms of proliferation and apoptosis both in vitro and in vivo, respectively. We also examined the functional mechanisms underlying the apoptotic pathways triggered by aloperine.ResultsAloperine induced MM cell death in a dose- and time-dependent manner, even in the presence of the proliferative cytokines interleukin-6 and insulin-like growth factor I. Mechanistic studies revealed that aloperine not only activated caspase-8 and reduced the expression of FADD-like interleukin-1β-converting enzyme (FLICE)-like inhibitory protein long (FLIPL) and FLICE-inhibitory proteins (FLIPS) but also activated caspase-9 and decreased the expression of phosphorylated (p)-PTEN. Moreover, co-activation of the caspase-8/cellular FLICE-inhibitory protein (cFLIP)- and caspase-9/p-PTEN/p-AKT-dependent apoptotic pathways by aloperine caused irreversible inhibition of clonogenic survival. Aloperine induce more MM apoptosis with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or borterzomib. A U266 xenograft tumor model and 5T33 MM cells recapitulated the antitumor efficacy of aloperine, and the animals displayed excellent tolerance of the drug and few adverse effects.ConclusionsAloperine has multifaceted antitumor effects on MM cells. Our data support the clinical development of aloperine for MM therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-015-0120-x) contains supplementary material, which is available to authorized users.

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