Abstract
In spite of recent therapeutic advances, multiple myeloma (MM) remains a malignancy with very low curability. This has been partly attributed to the existence of a drug-resistant subpopulation known as cancer stem cells (CSCs). MM-CSCs are equipped with the necessary tools that render them highly resistant to virtually all conventional therapies. In this study, the growth inhibitory effects of withanolide D (WND), a steroidal lactone isolated from Withania somnifera, on drug-sensitive tumoral plasma cells and drug-resistant MM cells have been investigated. In MTT/XTT assays, WND exhibited similar cytostatic effects between drug-resistant and drug-sensitive cell lines in the nM range. WND also induced cell death and apoptosis in MM-CSCs and RPMI 8226 cells, as examined by the calcein/ethidium homodimer and annexin V/propidium iodide stainings, respectively. To determine whether P-glycoprotein (P-gp) efflux affected the cytostatic activity of WND, P-gp was inhibited with verapamil and results indicated that the WND cytostatic effect in MM-CSCs was independent of P-gp efflux. Furthermore, WND did not increase the accumulation of the fluorescent P-gp substrate rhodamine 123 in MM-CSCs, suggesting that WND may not inhibit P-gp at the tested relevant doses. Therefore, the WND-induced cytostatic effect may be independent of P-gp efflux. These findings warrant further investigation of WND in MM-CSC animal models.
Highlights
Multiple myeloma is a plasma cells (PCs) neoplasm that accounts for 13% of hematological malignancies, and 1% of all cancers (Franqui-Machin et al, 2015)
Results indicated that a 72 h withanolide D (WND) treatment inhibited MMCSCs growth with an IC50 value of 88.4 ± 13.9 nM, and that of RPMI cells (RPMIs) with an IC50 of 76.1 ± 8.0 nM (Table 1)
Statistical analysis indicated that the IC50 values of WND were similar between MM-cancer stem cells (CSCs) and RPMIs, and between MM1.S and MM1.R cells
Summary
Multiple myeloma is a PC neoplasm that accounts for 13% of hematological malignancies, and 1% of all cancers (Franqui-Machin et al, 2015). WND Inhibits Myeloma Cell Growth into drug-resistant refractory myeloma, where therapeutic options become very limited (Franqui-Machin et al, 2015). CSCs can be identified based on surface stem cell markers such as CD44, CD133 or CD166, as well as on functional assays that measure the ability of CSCs to detoxify their intracellular environment. This ability is attributed to the high expression of metabolic enzymes such as aldehyde dehydrogenase and to ABC efflux transporters, a characteristic that renders MM-CSCs highly resistant to virtually all conventional MM therapies (Dean et al, 2005; Januchowski et al, 2013)
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