Piperlongumine induces apoptosis and reduces bortezomib resistance by inhibiting STAT3 in multiple myeloma cells

Yao, Yao; Sun, Yueyue; Shi, Min; Xia, Dandan; Zhao, Kai; Zeng, Lingyu; Yao, Ruosi; Zhang, Ying; Li, Zhenyu; Niu, Mingshan; Xu, Kailin

doi:10.18632/oncotarget.11988

Cited by 26 publications

(19 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…STAT3 inhibition stunts tumour growth by inducing cell apoptosis in many types of malignant tumours [ 19 , 20 ]. OS cell apoptosis was examined to investigate the mechanism underlying the effects of the STAT3 siRNA treatment.…”

Section: Resultsmentioning

confidence: 99%

Adipose-derived mesenchymal stem cells promote osteosarcoma proliferation and metastasis by activating the STAT3 pathway

et al. 2017

View full text Add to dashboard Cite

Osteosarcoma is the most common primary bone malignancy in children and young adults, but the role of adipose-derived mesenchymal stem cells (ADSCs) in the rapid progression of osteosarcoma is still unclear. Here, we found that ADSCs promoted tumour growth and invasion by increasing matrix metalloproteinase 2/9 (MMP2/9) expression in tumour cells. The persistent activation of signal transducer and activator of transcription 3 (STAT3) has been shown to directly promote tumour growth by mediating a wide spectrum of cellular responses, and STAT3 activation was detected in osteosarcoma cells co-cultured with ADSCs or treated with ADSC-conditioned medium. Furthermore, siRNA-mediated STAT3 inhibition in osteosarcoma cells decreased cell proliferation and invasion and down-regulated MMP2/9 expression. In addition, a nude mouse model of osteosarcoma was established by injecting luciferase-labelled MG63 cells into the tibia. As shown in in vivo bioluminescence images, ADSCs promoted tumour cell proliferation, invasion progression and metastasis. STAT3 inhibition attenuated tumour growth and metastasis and prolonged the survival of these mice. After the siRNA treatment, the MMP2, MMP9 and Ki67 levels decreased. Based on these data, stromal ADSCs promote osteosarcoma progression by increasing STAT3 signalling-mediated MMP2/9 expression.

show abstract

Section: Resultsmentioning

confidence: 99%

Adipose-derived mesenchymal stem cells promote osteosarcoma proliferation and metastasis by activating the STAT3 pathway

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Later, the anticancer potential of piplartine and its analogs, alone or in combination, including combination with paclitaxel, cisplatin, gemcitabine and curcumin, have been extensively explored [ 10 , 16 , 19 – 21 ]. These studies reported the ability of piplartine to induce apoptosis and/or autophagy through modulation of the PI3K/Akt/mTOR, NF-κB, JAK1,2/STAT3 and/or JNK pathways in cancer cells [ 14 , 15 , 22 – 24 ]. In addition, piplartine is a direct TrxR1 inhibitor and can inhibit cell migration/invasion via ROS/ER/MAPKs/CHOP axis [ 25 , 26 ].…”

Section: Introductionmentioning

confidence: 99%

Novel piplartine-containing ruthenium complexes: synthesis, cell growth inhibition, apoptosis induction and ROS production on HCT116 cells

Irs

et al. 2017

Oncotarget

View full text Add to dashboard Cite

Piplartine (piperlongumine) is a plant-derived molecule that has been receiving intense interest due to its anticancer characteristics that target the oxidative stress. In the present paper, two novel piplartine-containing ruthenium complexes [Ru(piplartine)(dppf)(bipy)](PF6)2 (1) and [Ru(piplartine)(dppb)(bipy)](PF6)2 (2) were synthesized and investigated for their cellular and molecular responses on cancer cell lines. We found that both complexes are more potent than metal-free piplartine in a panel of cancer cell lines on monolayer cultures, as well in 3D model of cancer multicellular spheroids formed from human colon carcinoma HCT116 cells. Mechanistic studies uncovered that the complexes reduced the cell growth and caused phosphatidylserine externalization, internucleosomal DNA fragmentation, caspase-3 activation and loss of the mitochondrial transmembrane potential on HCT116 cells. Moreover, the pre-treatment with Z-VAD(OMe)-FMK, a pan-caspase inhibitor, reduced the complexes-induced apoptosis, indicating cell death by apoptosis through caspase-dependent and mitochondrial intrinsic pathways. Treatment with the complexes also caused a marked increase in the production of reactive oxygen species (ROS), including hydrogen peroxide, superoxide anion and nitric oxide, and decreased reduced glutathione levels. Application of N-acetyl-cysteine, an antioxidant, reduced the ROS levels and apoptosis induced by the complexes, indicating activation of ROS-mediated apoptosis pathway. RNA transcripts of several genes, including gene related to the cell cycle, apoptosis and oxidative stress, were regulated under treatment. However, the complexes failed to induce DNA intercalation. In conclusion, the complexes are more potent than piplartine against different cancer cell lines and are able to induce caspase-dependent and mitochondrial intrinsic apoptosis on HCT116 cells by ROS-mediated pathway.

show abstract

“…STAT3 has been reported to be constitutively active in MM patients [ 22 , 54 , 55 ]. Pharmacological agents such as curcumin, piperlongumine, icaritin and LLL12 which blocked STAT3 phosphorylation were reported to suppress primary MM cell viability and/or MM tumor growth in animal models [ 22 , 56 , 57 , 58 ]. Clinically, a high pSTAT3 level has been reported to correlate with poorer progress-free survival and overall survival in newly diagnosed MM patients [ 59 ].…”

Section: Discussionmentioning

confidence: 99%

Constitutive Activation of STAT3 in Myeloma Cells Cultured in a Three-Dimensional, Reconstructed Bone Marrow Model

Huang

Molavi

Alshareef

et al. 2018

Cancers

View full text Add to dashboard Cite

Malignant cells cultured in three-dimensional (3D) models have been found to be phenotypically and biochemically different from their counterparts cultured conventionally. Since most of these studies employed solid tumor types, how 3D culture affects multiple myeloma (MM) cells is not well understood. Here, we compared MM cells (U266 and RPMI8226) in a 3D culture model with those in conventional culture. While the conventionally cultured cells were present in single cells or small clusters, MM-3D cells grew in large spheroids. We discovered that STAT3 was the pathway that was more activated in 3D in both cell lines. The active form of STAT3 (phospho-STAT3 or pSTAT3), which was absent in MM cells cultured conventionally, became detectable after 1–2 days in 3D culture. This elevated pSTAT3 level was dependent on the 3D environment, since it disappeared after transferring to conventional culture. STAT3 inhibition using a pharmacological agent, Stattic, significantly decreased the cell viability of MM cells and sensitized them to bortezomib in 3D culture. Using an oligonucleotide array, we found that 3D culture significantly increased the expression of several known STAT3 downstream genes implicated in oncogenesis. Since most primary MM tumors are naturally STAT3-active, studies of MM in 3D culture can generate results that are more representative of the disease.

show abstract

Piperlongumine induces apoptosis and reduces bortezomib resistance by inhibiting STAT3 in multiple myeloma cells

Cited by 26 publications

References 41 publications

Adipose-derived mesenchymal stem cells promote osteosarcoma proliferation and metastasis by activating the STAT3 pathway

Adipose-derived mesenchymal stem cells promote osteosarcoma proliferation and metastasis by activating the STAT3 pathway

Novel piplartine-containing ruthenium complexes: synthesis, cell growth inhibition, apoptosis induction and ROS production on HCT116 cells

Constitutive Activation of STAT3 in Myeloma Cells Cultured in a Three-Dimensional, Reconstructed Bone Marrow Model

Contact Info

Product

Resources

About