Luteolin inhibits the TGF-ß signaling pathway to overcome bortezomib resistance in multiple myeloma.

Multiple myeloma (MM) is an incurable condition and the second most common hematological malignancy. Over the past few years, there has been progress in the treatment of MM, but most patients still relapse. Multiple myeloma stem-like cells (MMSCs) are believed to be the main reason for drug resistance and eventual relapse. Currently, there are not enough therapeutic agents that have been identified for eradication of MMSCs, and thus, identification of the same may alleviate the issue of relapse in patients. In the present study, we showed that luteolin (LUT), a natural compound obtained from different plants, such as vegetables, medicinal herbs, and fruits, effectively inhibits the proliferation of MM cells and overcomes bortezomib (BTZ) resistance in them in vitro and in vivo, mainly by decreasing the proportion of ALDH1+ cells. Furthermore, RNA sequencing after LUT treatment of MM cell lines and an MM xenograft mouse model revealed that the effects of the compound are mediated through inhibition of transforming growth factor-ß signaling. Similarly, we found that LUT also significantly reduced the proportion of ALDH1+ cells in primary CD138+ plasma cells. In addition, LUT could overcome the BTZ treatment-induced increase in the proportion of ALDH1+ cells, and the combination of LUT and BTZ had a synergistic effect against myeloma cells. Collectively, our findings suggested that LUT is a promising agent that manifests MMSCs to overcome BTZ resistance, alone or in combination with BTZ, and thus, is a potential therapeutic drug for the treatment of MM.

Anti-BCMA surface engineered biomimetic photothermal nanomissile enhances multiple myeloma cell apoptosis and overcomes the disturbance of NF-κB signaling in vivo.

Conventional chemotherapy for multiple myeloma (MM) faces the challenges of a low complete remission rate and transformation to recurrence/refractory. The current MM first-line clinical drug Bortezomib (BTZ) faces the problem of enhanced tolerance and nonnegligible side effects. B cell maturation antigen (BCMA), for its important engagement in tumor signaling pathways and novel therapy technologies such as Chimeric antigen receptor T-Cell immunotherapy (CAR-T) and Antibody Drug Conjugate (ADC), has been identified as an ideal target and attracted attention in anti-MM therapy. Emerging nanotechnology provided feasible methods for drug delivery and new therapeutic strategies such as photothermal therapy (PTT). Herein, we developed a BCMA-Targeting biomimetic photothermal nanomissile BTZ@BPQDs@EM @anti-BCMA (BBE@anti-BCMA) by integration of BTZ, black phosphorus quantum dots (BPQDs), Erythrocyte membrane (EM) and BCMA antibody (anti-BCMA). We hypothesized that this engineered nanomissile could attack tumor cells in triple ways and achieve effective treatment of MM. Consequently, the intrinsic biomimetic nature of EM and the active targeting property of anti-BCMA enhanced the accumulation of therapeutic agents in the tumor site. Besides, owing to the decrease in BCMA abundance, the potential apoptosis-inducing ability was revealed. With the support of BPQDs' photothermal effect, Cleaved-Caspase-3 and Bax signal increased significantly, and the expression of Bcl-2 was inhibited. Furthermore, the synergistic photothermal/chemo therapy can effectively inhibit tumor growth and reverse the disorder of NF-κB in vivo. Importantly, this biomimetic nanodrug delivery system and antibody induced synergistic therapeutic strategy efficiently killed MM cells with ignorable systemic toxicity, which is a promising method for the future anticancer treatment of hematological malignancies in clinics.

Polyphyllin VII, a novel moesin inhibitor, suppresses cell growth and overcomes bortezomib resistance in multiple myeloma.

Multiple myeloma is a plasma cell malignancy, accounting for approximately 1% of new cancer cases. It is the second most common hematological malignancy. Novel clinical agents such as the proteasome inhibitor-bortezomib, have shown improved survival rates in recent decades. However, multiple myeloma remains incurable, as most patients eventually relapse and become refractory to current treatments. Therefore, there is an urgent need for developing new regimens to overcome the bortezomib resistance. Here, we screened a library of 2370 bioactives and found that polyphyllin VII selectively suppressed multiple myeloma cell growth in vitro and in vivo. We identified moesin, one of the critical regulators of the Wnt/ß-catenin pathway, as a target of polyphyllin VII by drug affinity responsive target stability assay and cellular thermal shift assay. Polyphyllin VII binds to moesin and induces its degradation via the ubiquitin-proteasome pathway, thereby impairing the Wnt/ß-catenin pathway activity and leading to a reduction in the side population cells to overcome bortezomib resistance. Our study identified polyphyllin VII as a promising compound and moesin as a potential diagnostic and therapeutic target for treating multiple myeloma.