Diallyl thiosulfinate enhanced the anti-cancer activity of dexamethasone in the side population cells of multiple myeloma by promoting miR-127-3p and deactivating the PI3K/AKT signaling pathway

Abstract

Background Side population (SP) cells, which have similar features to those of cancer stem cells, show resistance to dexamethasone (Dex) treatment. Thus, new drugs that can be used in combination with Dex to reduce the population of SP cells in multiple myeloma (MM) are required. Diallyl thiosulfinate (DATS, allicin), a natural organosulfur compound derived from garlic, has been shown to inhibit the proliferation of SP cells in MM cell lines. Therefore, we investigated the effect of a combination of DATS and Dex (DAT + Dex) on MM SP cells. Methods SP cells were sorted from MM RPMI-8226 and NCI-H929 cell lines using Hoechst 33342-labeled fluorescence-activated cell sorting. The growth of SP cells was evaluated using the cell counting kit-8 assay. Cell cycle and apoptosis assays were conducted using a BD Calibur flow cytometer. miRNA expression was measured using quantitative reverse transcription-polymerase chain reaction. Phosphoinositide 3-kinase (PI3K), phosphorylated AKT (p-AKT), AKT, p-mechanistic target of rapamycin (mTOR), and mTOR levels were measured using western blot analysis. Results Our results showed that the combination of DATS+Dex inhibited sphere formation, colony formation, and proliferation of MM SP cells by inducing apoptosis and cell cycle arrest in the G1/S phase. In addition, the combination of DATS+Dex promoted miR-127-3p expression and inhibited PI3K, p-AKT, and p-mTOR expression in SP cells. Knockdown of miR-127-3p expression weakened the effect of DATS+Dex on cell proliferation, colony formation, apoptosis, and cell cycle of MM SP cells. Additionally, knockdown of miR-127-3p activated the PI3K/AKT/mTOR signaling pathway in MM SP cells cotreated with DATS+Dex. Conclusion We demonstrated that cotreatment with DATS+Dex reduced cell proliferation, promoted apoptosis, and caused cell cycle arrest of MM SP cells by promoting miR-127-3p expression and deactivating the PI3K/AKT/mTOR signaling pathway.

A Thiophene Derivative, 2‐Bromo‐5‐(2‐(methylthio)phenyl)thiophene, Has Effective Anticancer Potential with Other Biological Properties

“…The condensation of two sulfenic acids into thiosulfinates is a very rare event because of the abundancy of cellular thiols mostly in the form of glutathione [28,29] . Thiosulfinates and its derivatives are important anticancer agents [30–32] and the increase in their cellular concentration may well serve in cancer treatment as inhibitors of the proliferation of tumor cells via apoptosis [33] …”

“…[27] The condensation of two sulfenic acids into thiosulfinates is a very rare event because of the abundancy of cellular thiols mostly in the form of glutathione. [28,29] Thiosulfinates and its derivatives are important anticancer agents [30][31][32] and the increase in their cellular concentration may well serve in cancer treatment as inhibitors of the proliferation of tumor cells via apoptosis. [33] The cytotoxic activity of BMPT (Figure 1) was determined by MTT assay by using different cancer cell lines namely, prostate adenocarcinoma (LnCap), liver hepatocellular carcinoma (HepG2), colorectal adenocarcinoma (Caco-2) and noncancerous human cells (HEK293).…”

Role of MicroRNAs and Long Non-Coding RNAs in Sarcopenia

“…The enforced expression of miR-127 in a mouse model of muscular dystrophy ameliorated muscle disease [ 111 ]. In addition, miR-127 not only inhibits myoblast proliferation, but also functions as a tumor suppressor in several types of cancer [ 112 , 113 , 114 , 115 ]. This implies that miR-127 functions as an activator of cell differentiation and a suppressor of cell proliferation.…”

Identification and Characterization of Multiple Myeloma Stem Cell-Like Cells

“…In addition, natural products are considered biocompatible and reliable treatments for human cancer [ 33 , 34 ]. Diallyl thiosulfinatecan enhances the inhibitory effect of dexamethasone on SP cells [ 35 ]. Baicalein can downregulate ABCG2 expression and suppress SP cells [ 36 , 37 ].…”

“…Surprisingly, proteasome inhibitor BTZ can enhance the percent of ALDH1 + cells in glioblastoma, synovial sarcoma, pancreatic adenocarcinoma, and MM cells [ 42 , 50 ]. Furthermore, lycorine or wee1 kinase inhibitor MK1775 can decrease the rate of ALDH1 + cells in combination with BTZ [ 35 , 42 ]. However, the role of immunomodulators, other proteasome inhibitors, and other MM clinical drugs in ALDH has not yet been reported.…”