Targeting SIRT1 to inhibit the proliferation of multiple myeloma cells

Abstract

Multiple myeloma (MM) is the second most common hematopoietic malignancy and remains an incurable disease. Thus, novel drugs and therapeutic methods are required for patients with MM. The present study aimed to investigate the effect of sirtuin 1 (SIRT1) inhibitor cambinol on the proliferation and apoptosis of myeloma cell lines, RPMI8226 and U266. Moreover, the present study evaluated the underlying molecular mechanisms of proliferation inhibition and apoptosis induced by cambinol. A Cell Counting Kit-8 assay was used to measure the viability of RPMI8226 and U266 cells treated with cambinol. Apoptosis and the cell cycle were analyzed via flow cytometry. The expression levels of caspase-3, poly(ADP-ribose) polymerase 1 (PARP), p53, acetylated p53 (Ac-p53), Bcl-2, cyclin D1 and p21 were detected in cells treated with cambinol using western blot analysis. The results demonstrated that cambinol inhibited the proliferation of RPMI8226 and U266 cells in a time- and dose-dependent manner. Increased apoptosis and G 1 cell cycle arrest, together with enhanced procaspase-3 degradation and PARP cleavage were identified in cambinol-treated cells compared with controls. Western blotting results also revealed the upregulation of p53 acetylation and p21, as well as the downregulation of Bcl-2 and cyclin D1 in cells treated with cambinol. In conclusion, the present results suggest that cambinol inhibits the proliferation and induces apoptosis in RPMI8226 and U266 cells by regulating acetylation of p53 via the targeting of SIRT1.

Vorinostat (SAHA) and Breast Cancer: An Overview

“…The idea of treating BC patients with new active agents capable to re-establish expression of tumor suppressor genes, which are silenced by epigenetic mechanisms is being tested [67]. HDIs seem to be a promising group of anticancer drugs, particularly in combination with other anticancer agents [84,208] or radiotherapy [209,210]. So far, 4 HDIs have been approved by the US FDA for the treatment of certain types of hematological malignancy [67].…”

“…No sirtuin inhibitors have been approved by FDA so far. Preclinical studies indicate that some sirtuin inhibitors show promising in vitro results used alone against solid tumors [ 83 , 84 , 85 , 86 , 87 ]; however, the data obtained from combined-treatment research are controversial, concluding different types of pharmacological interactions between tested drugs [ 88 , 89 , 90 , 91 ].…”

Targeting the Interplay between HDACs and DNA Damage Repair for Myeloma Therapy

“…However, it has been shown that HDACs and SIRTs could deacetylate and other non-histone substrates modifying their action. Therefore, the targets of HDACs become important key-players in cellular biology with multiple functions and mode of action and consequently, the HDACs a very promising therapeutic strategy in multiple myeloma [ 33 , 36 , 115 , 116 ]. Some of the different functions of HDAC inhibitors in cancer are depicted in Figure 5 .…”

Sirtuin Modulators in Cellular and Animal Models of Human Diseases

“…In NCI-H460 lung cancer and HeLa cervical cancer cells, Cambinol increased acetylation levels of several sirtuin substrates, including p53, α-tubulin, FOXO3a, and Ku70 ( Heltweg et al, 2006 ). In RPMI8226 and U266 multiple myeloma cells, Cambinol induced apoptosis, cell proliferation impairment, and cell cycle arrest by increasing p53, p21, cleaved PARP, and cleaved caspase 3 ( Lu et al, 2021 ). In orthopedic tumor xenograft mice model with HepG2 hepatocarcinoma cells, Cambinol significantly reduced tumor growth, which was consistent with the SIRT1 knockdown results of in vivo intrahepatic xenograft mouse model ( Portmann et al, 2013 ).…”

“…- (Heltweg et al, 2006;Marshall et al, 2011;Portmann et al, 2013;Ceballos et al, 2021;Lu et al, (Grozinger et al, 2001;Mai et al, 2005;Ota et al, 2006;Kojima et al, 2008;Kozako et al, 2012;Fong et al, 2014;Zhou et al, 2014;Safari et al, 2017;Ma et al, 2018) -H1299 non-small lung and HeLa cervical: decreased cell proliferation (Lain et al, 2008;McCarthy et al, 2012;Dai et al, 2016;Spiegelman et al, 2018;Lee et al, 2019 or quercetin activated sirtuins (Aksoy et al, 2006;Lee, 2006;Escande et al, 2013). Because this review specifically summarizes modulators that directly bind to sirtuins, we will not explain these indirect modulators in detail.…”