Perifosine Induces Cell Apoptosis in Human Osteosarcoma Cells: New Implication for Osteosarcoma Therapy?

Yao, Chen; Wei, Jianjun; Wang, Zuyu; Ding, Huimin; Li, Dong; Yan, Shichang; Yang, Ye; Gu, Zhangping

doi:10.1007/s12013-012-9423-5

Cited by 45 publications

(21 citation statements)

References 39 publications

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“…For example, perifosine could activate pro-apoptotic JNK in various cancer cell lines [24,34,35]. Inhibition of JNK, both pharmacologically or genetically, then alleviated perifosine-induced cancer cell apoptosis [34,35]. Several studies demonstrated that perifosine could inhibit ERK activation, but that effect was cell line dependent [36,37].…”

Section: Discussionmentioning

confidence: 99%

Combination treatment with perifosine and MEK-162 demonstrates synergism against lung cancer cells in vitro and in vivo

2015

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Lung cancer is a global health problem. The search for new therapeutic approaches for the treatment of lung cancer is important. Here, we reported that the AKT inhibitor perifosine and the MEK\ERK inhibitor MEK-162 synergistically induced lung cancer cell (A549 and H460 lines) growth inhibition and apoptosis. The combined efficiency was significantly higher than either agent alone. For the molecular study, perifosine and MEK-162 worked together to concurrently block AKT, mammalian target of rapamycin (mTOR) complex 1 (mTORC1), and MEK-ERK signalings in lung cancer cells, while either agent alone only affected one or two signalings with lower efficiency. In vivo, MEK-162 and perifosine co-administration dramatically inhibited A549 lung cancer xenograft growth, without inducing apparent toxicities. The synergistic activity in vivo was again superior than either agent alone. Thus, perifosine and MEK-162 combination is biologically plausible by acting through effects on different proliferation and survival-related signaling pathways. Our in vitro and in vivo results support the feasibility of investigating the synergism regimen in clinical tests.

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Section: Discussionmentioning

confidence: 99%

Combination treatment with perifosine and MEK-162 demonstrates synergism against lung cancer cells in vitro and in vivo

2015

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“…U2OS and MG-63 osteoblastoma cells as well as HEK-293T were gifts from Dr. Zhang-Ping Gu at Nanjing Medical University [48,49], cells were maintained in DMEM (Sigma, St. Louis, MO), supplemented with a 10% FBS (Sigma) plus penicillin/streptomycin (1:100; Sigma), in a CO 2 incubator at 37 °C. …”

Section: Methodsmentioning

confidence: 99%

Salinomycin Activates AMP-Activated Protein Kinase-Dependent Autophagy in Cultured Osteoblastoma Cells: A Negative Regulator against Cell Apoptosis

et al. 2013

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BackgroundThe malignant osteoblastoma has poor prognosis, thus the search for novel and more efficient chemo-agents against this disease is urgent. Salinomycin induces broad anti-cancer effects both in vivo and in vitro, however, its role in osteoblastoma is still not clear. Key FindingsSalinomycin induced both apoptosis and autophagy in cultured U2OS and MG-63 osteoblastoma cells. Inhibition of autophagy by 3-methyladenine (3-MA), or by RNA interference (RNAi) of light chain 3B (LC3B), enhanced salinomycin-induced cytotoxicity and apoptosis. Salinomycin induced a profound AMP-activated protein kinase (AMPK) activation, which was required for autophagy induction. AMPK inhibition by compound C, or by AMPKα RNAi prevented salinomycin-induced autophagy activation, while facilitating cancer cell death and apoptosis. On the other hand, the AMPK agonist AICAR promoted autophagy activation in U2OS cells. Salinomycin-induced AMPK activation was dependent on reactive oxygen species (ROS) production in osteoblastoma cells. Antioxidant n-acetyl cysteine (NAC) significantly inhibited salinomycin-induced AMPK activation and autophagy induction. ConclusionsSalinomycin activates AMPK-dependent autophagy in osteoblastoma cells, which serves as a negative regulator against cell apoptosis. AMPK-autophagy inhibition might be a novel strategy to sensitize salinomycin’s effect in cancer cells.

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“…Nevertheless, despite not achieving the primary objectives related to significant increases in progression-free survival rates, some optimism still remained for this agent in advanced soft tissue sarcoma patients (Bailey, et al, 2006), as well as to warrant further evaluation of perifosine in combination with rituximab or other active agents in patients with relapsed/refractory Waldenstrom's macroglobulinemia (Ghobrial, et al, 2010), and with currently available therapies in renal cancer (Cho, et al, 2012). Furthermore, a number of studies have reported the potentiation of antitumor activity following combination of perifosine with distinct anticancer drugs in cancer cells derived from several types of leukemia (Nyakern, et al, 2006;Papa, et al, 2008;Tazzari, et al, 2008), multiple myeloma Hideshima, et al, 2006), osteosarcoma (Yao, et al, 2013), medulloblastoma (Kumar, et al, 2009), lung cancer (Elrod, et al, 2007), colon cancer (M. B. Chen, et al, 2012, and glioma (Momota, et al, 2005), as well as following combination of miltefosine with different anticancer compounds or treatments in distinct cancer cell types (Haberkorn, et al, 1992;Papagiannaros, et al, 2006;Spruss, et al, 1993;Thakur, et al, 2013). Thus, phase II clinical trials were conducted with…”

Section: Alkylphosphocholinesmentioning

confidence: 99%

Alkyl ether lipids, ion channels and lipid raft reorganization in cancer therapy

Jaffrès

Gajate

Bouchet

et al. 2016

Pharmacology & Therapeutics

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Synthetic alkyl lipids, such as the ether lipids edelfosine (1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine) and ohmline (1-O-hexadecyl-2-O-methyl-rac-glycero-3-β-lactose), are forming a class of antitumor agents that target cell membranes to induce apoptosis and to decrease cell migration/invasion, leading to the inhibition of tumor and metastasis development. In this review, we present the structure-activity relationship of edelfosine and ohmline, and we point out differences and similarities between these two amphiphilic compounds. We also discuss the mechanisms of action of these synthetic alkyl ether lipids (involving, among other structures and molecules, membrane domains, Fas/CD95 death receptor signaling, and ion channels), and highlight a key role for lipid rafts in the underlying process. The reorganization of lipid raft membrane domains induced by these alkyl lipids affects the function of death receptors and ion channels, thus leading to apoptosis and/or inhibition of cancer cell migration. The possible therapeutic use of these alkyl lipids and the clinical perspectives for these lipids in prevention or/and treatment of tumor development and metastasis are also discussed.

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Perifosine Induces Cell Apoptosis in Human Osteosarcoma Cells: New Implication for Osteosarcoma Therapy?

Cited by 45 publications

References 39 publications

Combination treatment with perifosine and MEK-162 demonstrates synergism against lung cancer cells in vitro and in vivo

Combination treatment with perifosine and MEK-162 demonstrates synergism against lung cancer cells in vitro and in vivo

Salinomycin Activates AMP-Activated Protein Kinase-Dependent Autophagy in Cultured Osteoblastoma Cells: A Negative Regulator against Cell Apoptosis

Alkyl ether lipids, ion channels and lipid raft reorganization in cancer therapy

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