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Feature Papers represent the most advanced research with the greatest potential for high impact in the field. Feature papers are submitted by invitation or individual recommendation by the scientific editors and are peer-reviewed before publication.
Migraine: Integrated Approaches To Clinical Management And Emerging Treatments
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Procaspase-Activating Compound-1 Synergizes with TRAIL to Induce Apoptosis in the Established Granulosa Cell Tumor Cell Line (KGN) and Explanted Granulosa Cell Tumor Cells In Vitro
By Powel Crosley 1 , Anniina Farkkila 2 , Adrianne L. Jenner 3, 4 , Chloé Burlot 3 , Olivia Cardinal 3 , Kyle G. Potts 1 , Kate Agopsowicz 1 , Marjut Pihlajoki 2 , Markku Heikinheimo , Morgan 6 Craig 6 Morgan 5 , Yangxin Fu 1 and Mary M. Hitt 1, *
Antibody Panels For Autoimmune And Paraneoplastic Disorders: A Pandora’s Box For Clinicians
Received: 10 March 2021 / Updated: 24 April 2021 / Accepted: 28 April 2021 / Published: 29 April 2021
Granulosa cell tumors (GCT) make up only ~5% of ovarian neoplasms but have a significant impact, as up to 80% of women with recurrent GCT will die of the disease. This study investigated the efficacy of procaspase-activating compound 1 (PAC-1), an activator of procaspase-3, in the treatment of adult GCT (AGCT) together with selected apoptosis-inducing agents. The sensitivity of the AGCT cell line KGN to these drugs, alone or in combination with PAC-1, was tested using a sensitivity assay. Our results show a wide range of cytotoxic activity among the agents tested. Synergy with PAC-1 was most pronounced, both qualitatively and quantitatively, when combined with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). This compound showed rapid kinetics of apoptosis induction as determined by caspase-3 activation, and strong synergistic killing of both KGN as well as primary and recurrent AGCT patient samples . We showed that a new combination of pro-apoptotic agents, TRAIL and PAC-1, significantly enhanced the induction of apoptosis in AGCT cells, providing further evidence for this combination as a potential treatment for AGCT .
Granulosa cell tumor (GCT) is a malignant stromal cell type of ovarian cancer that accounts for ~5% of ovarian neoplasms [ 1 ]. The majority (89%) of cases are primary GCT [2], however they present chaos: although five-year survival is >90%, GCT is known to relapse and ~80% of women those who relapse will die of this disease [1, 3]. Surgery is the mainstay of treatment and European and American clinical guidelines recommend platinum-based therapies if chemotherapy is appropriate [4, 5]. However, many recent case history reviews have shown no survival advantage between adjuvant chemotherapy, radiotherapy and observation [6, 7]. There are two types of GCT, adult (AGCT) and pediatric GCT, and 95% of GCTs are AGCT [2]. In 2009, Shah et al., discovered a unique somatic mutation (FOXL2C134W) that was present in 97% of AGCT cases and in the only available cell line derived from AGCT, KGN [8] .
Recently, there have been reports of drug testing studies involving AGCT (KGN and/or human tumor cells). A high-level study reported by Haltia et al. demonstrated the sensitivity of AGCT to the tyrosine kinase inhibitor dasatinib and the mTOR inhibitor everolimus that act similarly to the microtubule-targeted chemotherapeutic agent paclitaxel [ 9 ]. Rose et al. evaluated the responses of patient-derived AGCT cell cultures to 11 monotherapies and 12 combination therapies. None of the monotherapies tested were very effective, but their study shows the possibility of combining carboplatin, paclitaxel, and the kinase inhibitor alpelisib for the treatment of this disease [7].
Autonomous Role Of Wiskott Aldrich Syndrome Platelet Deficiency In Inducing Autoimmunity And Inflammation
We took another approach to evaluate a new combination of drugs for treating AGCT, with a focus on facilitating apoptosis of tumor cells. One of the main methods of killing tumor cells with anti-cancer drugs is the induction of “programmed cell death”, apoptosis. Apoptosis is activated as a result of irreparable DNA damage, external stimuli, or other cellular stresses, and the apoptotic pathway eventually changes from the activation of procaspase-3 to caspase-3 , which is the primary cause of apoptosis. Many chemicals overexpress procaspase-3 and are balanced by caspase-3 inhibitors in order to survive [10]. Caspase-3 activity is also regulated by Zn
, which is reported to have three caspase-3 binding sites [11]. Although the exact effects of multiple binding sites are unclear, it is thought that Zn
Blocks access to the active site (near His121) and may interfere with access to the Ile-Glu-Thr-Asp175 cleavage site (IETD)
) (Figure S1) [11, 12]. Procaspase activating compound-1 (PAC-1) is a small molecule compound that was identified in a high-throughput screen of ~20,500 small molecule compounds for the ability to activate procaspase-3 in vitro [ 10]. Later, it was determined that PAC-1 prepares procaspase-3 for activity by inhibiting the labile inhibitory Zn.
Pdf) Immunohistochemical Characterization Of Procaspase 3 Overexpression As A Druggable Target With Pac 1, A Procaspase 3 Activator, In Canine And Human Brain Cancers
Ions from the zymogen, which allows it to enter the active state or to be cleaved by the initiator caspases, caspase-8 and caspase-9 [13]. The ability of caspase-3 to develop spontaneously means that the capture of Zn
It can activate apoptosis even when the upstream signals are not faulty, in a way that is proportional to the pressure of procaspase-3 in the cell, which explains the choice of PAC-1 for cancer [10]. PAC-1 has shown efficacy as an anti-cancer agent in vitro and in vivo, and has limited activity on other zinc-dependent enzymes [14], which may be partially responsible specific for its demonstrated safety. PAC-1 is being investigated in phase I trials for advanced disease (NCT02355535, NCT03332355).
Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) is a transmembrane protein that binds to receptor-4 or -5 (DR4/DR5) that triggers the extrinsic apoptotic pathway as well as the intrinsic pathway through caspase-8 truncation of BID [15, 16]. TRAIL induces apoptosis in cancer cells without being toxic to normal cells and has been clinically well tolerated by patients [17, 18, 19]. However, surprisingly, clinical trials with soluble TRAIL have failed to show efficacy [20]. Potential limiting factors include in vivo half-life, inability to achieve therapeutic concentrations at the tumor site, and down-regulation of death receptors or mediators of apoptosis [21].
Interestingly, normal granulosa cells and most GCTs express DR4/5 [1, 22] and the GCT cell line KGN has been reported to be sensitive to TRAIL in vitro when combined with cisplatin, proteasome inhibitors, or mitochondrial membrane that may be uncouplers [23, 24]. ]. Here, we report that the procaspase-3-activator PAC-1 interacts with TRAIL to kill both KGN cells and four independent patient-derived GCT cultures, but not normal cells, by induction of apoptosis. We also report that the PAC-1/TRAIL combination appears to be more effective than PAC-1 combined with the chemotherapy drugs carboplatin or gemcitabine, or embelin, an inhibitor of X-linked inhibitor of apoptosis protein (XIAP), without increased sensitivity. normal cells. We propose that the PAC-1/TRAIL combination should continue to be investigated as a treatment option for patients with GCT.
A Basomedial Amygdala To Intercalated Cells Microcircuit Expressing Pacap And Its Receptor Pac1 Regulates Contextual Fear
Like many other tumor cells [7], the only available AGCT cell line, KGN, expresses appreciable levels of caspase-3 (Figure S2). We examined whether this property could be exploited to induce KGN cell death by treating with increasing concentrations of PAC-1 up to 40 µM (Figure 1A). At higher doses than this, PAC-1 has been reported to induce killing independent of procaspase-3 and caspase-3 [25]. This reaction test for activation, confirmed by visual inspection of cell cultures, showed PAC-1 sensitivity of KGN cells. Cytotoxicity appeared to be partially dependent on caspase-3, as killing was reduced in KGN cells transfected with shRNA targeting caspase-3 compared to KGN cells transfected with control shRNA (Figure S2).
We then compared the response of KGN and PAC-1 cells to responses to a group of apoptosis-inducing agents that act upstream of caspase-3, a target of PAC-1. Common chemotherapeutic agents, namely carboplatin (alkylating agent) and gemcitabine (nucleoside analog), interfere with DNA replication, activating the DNA damage response [24] and subsequent subsequent apoptosis. In turn, TRAIL binds to cell death receptors and activates caspase-3 in the intrinsic and extrinsic apoptotic pathways. Embelin is a SMAC-mimetic that inhibits XIAP, an inhibitor of caspase-3. Appropriate dosages of medication were selected for this study, based on established dosage guidelines or the results of ongoing clinical trials, with an evaluation of its efficacy.
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