Drug and Solute Transporters in Mediating Resistance to Novel Therapeutics in Multiple Myeloma

Mynott, Rachel Lauris; Wallington-Beddoe, Craig T.

doi:10.1021/acsptsci.1c00074

Cited by 13 publications

(10 citation statements)

References 135 publications

(345 reference statements)

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“…The new derivatives, because of the reduced polarity of the molecule in comparison to melphalan, may have wider delivery strategies. EM-T-MEL, EM-I-MEL, or EM-MORPIP-MEL can be transported to cancer cells by other membrane receptors that are overexpressed in leukemia cancer cells: MCT-1, -2, and -4, for lactate transport; OAT-1, for small, hydrophilic organic anion transport; OCTN-1, FLIPT-1, and OCT-6, for organic cation transport; and OATP1B1 and OATP1B3, for large, hydrophobic anion transport [29]. P2X7R, an ATP-gated ion channel, is widespread in cancer cells and overexpressed in AML.…”

Section: Discussionmentioning

confidence: 99%

Synthesis and In Vitro Activity of Novel Melphalan Analogs in Hematological Malignancy Cells

Poczta

Krzeczyński

Tobiasz

et al. 2022

IJMS

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Despite the continuous developments in pharmacology and the high therapeutic effect of new treatment options for patients with hematological malignancies, these diseases remain a major health issue. Our study aimed to synthesize, analyze in silico, and determine the biological properties of new melphalan derivatives. We obtained three methyl esters of melphalan having in their structures amidine moieties substituted with thiomorpholine (EM–T–MEL), indoline (EM–I–MEL), or 4–(4–morpholinyl) piperidine (EM–MORPIP–MEL). These have not yet been described in the literature. The in vitro anticancer properties of the analogs were determined against THP1, HL60, and RPMI8226 cells. Melphalan derivatives were evaluated for cytotoxicity (resazurin viability assay), genotoxicity (alkaline comet assay), and their ability to induce apoptosis (Hoechst33342/propidium iodide double staining method; phosphatidylserine translocation; and caspase 3/7, 8, and 9 activity measurements). Changes in mitochondrial membrane potential were examined using the specific fluorescence probe JC–1 (5,5′,6,6′–tetrachloro–1,1′,3,3′–tetraethylbenzimidazol carbocyanine). The EM–T–MEL derivative had the highest biological activity, showing higher cytotoxic and genotoxic properties than the parent drug. Moreover, it showed a high ability to induce apoptosis in the tested cancer cells. This compound also had a beneficial effect in peripheral blood mononuclear cells (PBMC). In conclusion, we verified and confirmed the hypothesis that chemical modifications of the melphalan structure improved its anticancer properties. The conducted study allowed the selection of the compound with the highest biological activity and provided a basis for chemical structure–biological activity analyses.

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Section: Discussionmentioning

confidence: 99%

Synthesis and In Vitro Activity of Novel Melphalan Analogs in Hematological Malignancy Cells

Poczta

Krzeczyński

Tobiasz

et al. 2022

IJMS

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“…Overall, our data suggested that genetic overexpression of SLC19A1 is correlated with inferior prognosis in MM. Previous studies revealed that solute carrier (SLC) transporters play an important role in MM drug resistance, including resistance to novel therapies (44). SLC19A1 belongs to the solute carrier (SLC) group of transporters and is the main mechanism by which folates and antifolate drugs are delivered to mammalian cells and tissues (45).…”

Section: Discussionmentioning

confidence: 99%

Hypoxia–Immune-Related Gene SLC19A1 Serves as a Potential Biomarker for Prognosis in Multiple Myeloma

Yuan

Liu

et al. 2022

Front. Immunol.

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BackgroundMultiple myeloma (MM) remains an incurable malignant tumor of plasma cells. Increasing evidence has reported that hypoxia and immune status contribute to the progression of MM. In this research, the prognostic value of the hypoxia–immune-related gene SLC19A1 in MM was evaluated by bioinformatics analysis.MethodRNA-sequencing (RNA-seq) data along with clinical information on MM were downloaded from the Gene Expression Omnibus (GEO) database. Consistent clustering analysis and ESTIMATE algorithms were performed to establish the MM sample subgroups related to hypoxia and immune status, respectively, based on the GSE24080 dataset. The differentially expressed analysis was performed to identify the hypoxia–immune-related genes. Subsequently, a hypoxia–immune-gene risk signature for MM patients was constructed by univariate and multivariate Cox regression analyses, which was also verified in the GSE4581 dataset. Furthermore, the mRNA expression of SLC19A1 was determined using qRT-PCR in 19 MM patients, and the correlations between the genetic expression of SLC19A1 and clinical features were further analyzed.ResultA total of 47 genes were identified as hypoxia–immune-related genes for MM. Among these genes, SLC19A1 was screened to construct a risk score model that had better predictive power for MM. The constructed prognostic signature based on SLC19A1 was verified in the GSE4581 dataset. All independent prognostic factors (age, β2-microglobulin, LDH, albumin, MRI, and gene risk score) were used to develop a nomogram that showed a better performance for predicting the survival probability of MM patients for 1–5 years. Furthermore, SLC19A1 was highly expressed in newly diagnosed and relapsed MM patients, and high expression of SLC19A1 is correlated with higher bone marrow aspiration plasma cells and β2-microglobulin levels in MM patients.ConclusionIn conclusion, our results suggest that SLC19A1 is aberrantly expressed in MM and highly expressed SLC19A1 might be a biomarker correlated with inferior prognosis. More importantly, we identified SLC19A1 as a hypoxia–immune-related gene in MM. Future functional and mechanistic studies will further clarify the roles of SLC19A1 in MM.

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“…Therefore, methods that down-regulate or inhibit GCS might be expected to re-sensitize cancer cells to therapeutic drugs. In myeloma patients and MM cell lines, treatments with classic chemotherapeutic drugs, such as doxorubicin and melphalan, have been reported to upregulate ABCB1 expression, which contributes to the development of resistance to these drugs ( 198 ). However, it’s unclear if the upregulation of ABCB1 in these cells results from increased GCS.…”

Section: Sphingolipids As Mediators Of Drug-resistance In MMmentioning

confidence: 99%

Role of Sphingolipids in Multiple Myeloma Progression, Drug Resistance, and Their Potential as Therapeutic Targets

2022

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Multiple myeloma (MM) is an incapacitating hematological malignancy characterized by accumulation of cancerous plasma cells in the bone marrow (BM) and production of an abnormal monoclonal protein (M-protein). The BM microenvironment has a key role in myeloma development by facilitating the growth of the aberrant plasma cells, which eventually interfere with the homeostasis of the bone cells, exacerbating osteolysis and inhibiting osteoblast differentiation. Recent recognition that metabolic reprograming has a major role in tumor growth and adaptation to specific changes in the microenvironmental niche have led to consideration of the role of sphingolipids and the enzymes that control their biosynthesis and degradation as critical mediators of cancer since these bioactive lipids have been directly linked to the control of cell growth, proliferation, and apoptosis, among other cellular functions. In this review, we present the recent progress of the research investigating the biological implications of sphingolipid metabolism alterations in the regulation of myeloma development and its progression from the pre-malignant stage and discuss the roles of sphingolipids in in MM migration and adhesion, survival and proliferation, as well as angiogenesis and invasion. We introduce the current knowledge regarding the role of sphingolipids as mediators of the immune response and drug-resistance in MM and tackle the new developments suggesting the manipulation of the sphingolipid network as a novel therapeutic direction for MM.

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Drug and Solute Transporters in Mediating Resistance to Novel Therapeutics in Multiple Myeloma

Cited by 13 publications

References 135 publications

Synthesis and In Vitro Activity of Novel Melphalan Analogs in Hematological Malignancy Cells

Synthesis and In Vitro Activity of Novel Melphalan Analogs in Hematological Malignancy Cells

Hypoxia–Immune-Related Gene SLC19A1 Serves as a Potential Biomarker for Prognosis in Multiple Myeloma

Role of Sphingolipids in Multiple Myeloma Progression, Drug Resistance, and Their Potential as Therapeutic Targets

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