Small Compound 6-O-Angeloylplenolin Induces Mitotic Arrest and Exhibits Therapeutic Potentials in Multiple Myeloma

Abstract

BackgroundMultiple myeloma (MM) is a disease of cell cycle dysregulation while cell cycle modulation can be a target for MM therapy. In this study we investigated the effects and mechanisms of action of a sesquiterpene lactone 6-O-angeloylplenolin (6-OAP) on MM cells.Methodology/Principal FindingsMM cells were exposed to 6-OAP and cell cycle distribution were analyzed. The role for cyclin B1 to play in 6-OAP-caused mitotic arrest was tested by specific siRNA analyses in U266 cells. MM.1S cells co-incubated with interleukin-6 (IL-6), insulin-like growth factor-I (IGF-I), or bone marrow stromal cells (BMSCs) were treated with 6-OAP. The effects of 6-OAP plus other drugs on MM.1S cells were evaluated. The in vivo therapeutic efficacy and pharmacokinetic features of 6-OAP were tested in nude mice bearing U266 cells and Sprague-Dawley rats, respectively. We found that 6-OAP suppressed the proliferation of dexamethasone-sensitive and dexamethasone-resistant cell lines and primary CD138+ MM cells. 6-OAP caused mitotic arrest, accompanied by activation of spindle assembly checkpoint and blockage of ubiquitiniation and subsequent proteasomal degradation of cyclin B1. Combined use of 6-OAP and bortezomib induced potentiated cytotoxicity with inactivation of ERK1/2 and activation of JNK1/2 and Casp-8/-3. 6-OAP overcame the protective effects of IL-6 and IGF-I on MM cells through inhibition of Jak2/Stat3 and Akt, respectively. 6-OAP inhibited BMSCs-facilitated MM cell expansion and TNF-α-induced NF-κB signal. Moreover, 6-OAP exhibited potent anti-MM activity in nude mice and favorable pharmacokinetics in rats.Conclusions/SignificanceThese results indicate that 6-OAP is a new cell cycle inhibitor which shows therapeutic potentials for MM.

Potential molecular targets for inhibiting bone invasion by oral squamous cell carcinoma: a review of mechanisms

“…It also induced G1-phase cell-cycle arrest and apoptosis through inactive Akt and mitochondrial oxidative stress in cells of nasopharyngeal carcinoma [85]. The latter demonstrates the bio-effect of anti-cancer on inhibiting the proliferation of cancer cells in human colorectum, liver, stomach, lung and skin cancers [86], and on inducing cell apoptosis through a mitochondrial/caspase and NF-κB pathway in human HL-60 leukaemia and myeloma [87,88].…”

Identification of an Annonaceous Acetogenin Mimetic, AA005, as an AMPK Activator and Autophagy Inducer in Colon Cancer Cells

“…MTT assay was performed as described [31], and the IC 50 values were calculated using the CalcuSyn software (version 2.0, Biosoft, Cambridge, UK). Cell viability was estimated by trypan blue dye exclusion.…”

Small compound 6-O-angeloylplenolin induces caspase-dependent apoptosis in human multiple myeloma cells

“…In addition, 6-OAP was identified to inhibit the Jak2/Stat3 and Akt signaling pathways, thereby blocking the facilitation of the BM microenvironment on the MM cells. 6-OAP has also been found to induce marked inhibition of NF-κB in MM cells (5). However, to date, no studies have determined whether the inhibitory effects of 6-OAP on the cell cycle and certain signal pathways ultimately result in apoptosis.…”

“…The results of our preliminary study demonstrated that 6-OAP inhibits the proliferation of human MM cells by inducing the arrest of mitosis and inhibiting specific key pathways (5). However, whether 6-OAP-induced mitosis arrest and pathway inhibition are followed by apoptosis requires further study.…”