Sigma 1 Receptor antagonist potentiates the anti-cancer effect of p53 by regulating ER stress, ROS production, Bax levels, and caspase-3 activation

Happy, Mireille; Dejoie, Jordan; Zajac, Cynthia; Cortez, Briseida; Chakraborty, Karabi; Aderemi, Joseph; Sauane, Moira

doi:10.1016/j.bbrc.2014.12.029

Cited by 34 publications

(29 citation statements)

References 31 publications

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“…The mechanism of this protection may include NF-jB and/or extracellular signal-regulated kinase (ERK) pathways (Ha et al 2014;Meunier and Hayashi 2010). Another study demonstrated that Sig1-R may promote cell survival via the regulation of ER stress, p38 MAPK activation, ROS production, and proteins involved in apoptosis (Caspases-3, Bax) in breast cancer cells (Happy et al 2015). In a TBI model, Dong et al found that PRE-084 can significantly reduce lesion volume, lessen brain edema, and accelerate the recovery of nerve function and body weight after TBI, which indicated that MAMs may play an important role in cell fate and neural function following TBI (Dong et al 2016).…”

Section: Sig1-rmentioning

confidence: 97%

Potential Roles of Mitochondria-Associated ER Membranes (MAMs) in Traumatic Brain Injury

Sun

Chen

et al. 2017

Cell Mol Neurobiol

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The endoplasmic reticulum (ER) and mitochondria have both been shown to be critical in cellular homeostasis. The functions of the ER and mitochondria are independent but interrelated. These two organelles could form physical interactions, known as MAMs, to regulate physiological functions between ER and mitochondria to maintain Ca, lipid, and metabolite exchange. Several proteins are located in MAMs, including RNA-dependent protein kinase (PKR)-like ER kinase, inositol 1,4,5-trisphosphate receptors, phosphofurin acidic cluster sorting protein-2 and sigma-1 receptor to ensure regulation. Recent studies indicated that MAMs participate in inflammation and apoptosis in various conditions. All of these functions are crucial in determining cell fate following traumatic brain injury (TBI). We hypothesized that MAMs may associate with TBI and could contribute to mitochondrial dysfunction, ER stress, autophagy dysregulation, dysregulation of Ca homeostasis, and oxidative stress. In this review, we summarize the latest understanding of MAM formation and their potential regulatory role in TBI pathophysiology.

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Section: Sig1-rmentioning

confidence: 97%

Potential Roles of Mitochondria-Associated ER Membranes (MAMs) in Traumatic Brain Injury

Sun

Chen

et al. 2017

Cell Mol Neurobiol

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“…47) Sigma-1 receptor agonists and antagonists have been candidates as drugs for the sigma-1 related diseases mentioned above. 48,49) Therefore, imaging using radiolabeled probes to determine the sigma-1 receptor expression could become a companion diagnostic test of therapeutic agents targeting this receptor. In this review, I introduced some radiolabeled sigma-1 receptor targeting probes.…”

Section: Sigma-1 Receptor Targeted Probesmentioning

confidence: 99%

Development of Diagnostic and Therapeutic Probes with Controlled Pharmacokinetics for Use in Radiotheranostics

Ogawa

2019

CHEMICAL & PHARMACEUTICAL BULLETIN

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The word "theranostics," a portmanteau word made by combining "therapeutics" and "diagnostics," refers to a personalized medicine concept. Recently, the word, "radiotheranostics," has also been used in nuclear medicine as a term that refer to the use of radioisotopes for combined imaging and therapy. For radiotheranostics, a diagnostic probe and a corresponding therapeutic probe can be prepared by introducing diagnostic and therapeutic radioisotopes into the same precursor. These diagnostic and therapeutic probes can be designed to show equivalent pharmacokinetics, which is important for radiotheranostics. As imaging can predict the absorbed radiation dose and thus the therapeutic and side effects, radiotheranostics can help achieve the goal of personalized medicine. In this review, I discuss the use of radiolabeled probes targeting bone metastases, sigma-1 receptor, and α V β 3 integrin for radiotheranostics.

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“…Despite the evidence supporting the importance of S1R in cancer, the mechanism of action of S1R antagonists in causing cell death is still unclear. Currently, it has been hypothesized that the observed apoptototic phenomena are related to the increase of intracellular calcium levels [14][15][16].…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Synthesis and biological evaluation of new aryl-alkyl(alkenyl)-4-benzylpiperidines, novel Sigma Receptor (SR) modulators, as potential anticancer-agents

Rui

Rossi

Marra

et al. 2016

European Journal of Medicinal Chemistry

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In the early 2000s, the Sigma Receptor (SR) family was identified as potential "druggable" target in cancer treatment. Indeed, high density of SRs was found in breast, lung, and prostate cancer cells, supporting the idea that SRs could play a role in tumor growth and progression. Moreover, a link between the degree of SR expression and tumor aggressiveness has been postulated, justified by the presence of SRs in high metastatic-potential cancer cells. As a consequence, considerable efforts have been devoted to the development of small molecules endowed with good affinity towards the two SR subtypes (S1R and S2R) with potential anticancer activity. Herein we report the synthesis and biological profile of aryl-alkyl(alkenyl)-4-benzylpiperidine derivatives-as novel potential anticancer drugs targeting SR. Among them, 3 (RC-106) exhibited a preclinical profile of antitumor efficacy on a panel of cell lines representative of different cancer types (i.e. Paca3, MDA-MB 231) expressing both SRs, and emerged as a hit compound of a new class of SRs modulators potentially useful for the treatment of cancer disease. Keywords Sigma Receptor (SR); pan-SR modulators; compound 3 (RC-106); S1R agonist/antagonist profile; potential anticancer property; apoptotic pathway. Recent studies describe how S2R ligands trigger a cell response which inhibit the activity of the P-glycoprotein, responsible for the active extrusion of anticancer drugs, leading to cell death. [17,18]. Moreover, the hypothesis of a correlation between S2R and Progesterone Receptor Membrane Component 1 (PGRMC1) [19,20] supports the idea that S2R may exert a critical role in tumorigenesis [18]. Indeed, the over-expression of PGRMC1 has been associated to tumor stage and to actively proliferating and invasive cancer cells [21]. It is also relevant that proliferating breast carcinoma cells express S2R up to ten times more than quiescent cells, and the degree of S2R expression has been correlated with tumor staging and grading [22-24]. The highest level of S2R has been detected in pancreatic cancer cell lines (Panc-02, Panc-01, CFPAC-1, AsPC-1) [25]. A recent study, carried out on mouse breast cancer (EMT-6) and human melanoma (MDA-MB-435) cell lines, demonstrate that siramesine (Fig. 1), a S2R selective ligand commonly used as reference compound, can induce cell death (with an EC 50 in both cell lines lower than 10 µM) by three different mechanisms: caspase activation, autophagy, and impaired cell-cycle progression [26]. In the same work, it has been also demonstrated that other S2R ligands, i.e. SV119, WC-26 and RHM-138 (Fig. 1), possess a cytotoxic

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Sigma 1 Receptor antagonist potentiates the anti-cancer effect of p53 by regulating ER stress, ROS production, Bax levels, and caspase-3 activation

Cited by 34 publications

References 31 publications

Potential Roles of Mitochondria-Associated ER Membranes (MAMs) in Traumatic Brain Injury

Potential Roles of Mitochondria-Associated ER Membranes (MAMs) in Traumatic Brain Injury

Development of Diagnostic and Therapeutic Probes with Controlled Pharmacokinetics for Use in Radiotheranostics

Synthesis and biological evaluation of new aryl-alkyl(alkenyl)-4-benzylpiperidines, novel Sigma Receptor (SR) modulators, as potential anticancer-agents

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