scholarly journals The targeted SMAC mimetic SW IV-134 augments platinum-based chemotherapy in pre-clinical models of ovarian cancer

2022 ◽  
Author(s):  
Pratibha S. Binder ◽  
Yassar M. Hashim ◽  
James Cripe ◽  
Tommy Buchanan ◽  
Abigail Zamorano ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Death ◽  
Combination Therapy ◽  
Cell Lines ◽  
Xenograft Model ◽  
Advanced Ovarian Cancer ◽  
Tumor Growth Rate ◽  
Tumor Cell Death ◽  
Patient Derived Xenograft ◽  
Platinum Based Chemotherapy

Abstract Background: Ovarian cancer is initially responsive to frontline chemotherapy. Unfortunately, it often recurs and becomes resistant to available therapies and the survival rate for advanced and recurrent ovarian cancer is unacceptably low. We thus hypothesized that it would be possible to achieve more durable treatment responses by combining cisplatin chemotherapy with SW IV-134, a cancer-targeted peptide mimetic and inducer of cell death. SW IV-134 is a recently developed small molecule conjugate linking a sigma-2 ligand with a peptide analog (mimetic) of the intrinsic death pathway activator SMAC (second-mitochondria activator of caspases). The sigma-2 receptor is overexpressed in ovarian cancer and the sigma-2 ligand portion of the conjugate facilitates cancer selectivity. The effector portion of the conjugate is expected to synergize with cisplatin chemotherapy and the cancer selectivity is expected to reduce putative off-target toxicities. Methods: Ovarian cancer cell lines were treated with cisplatin alone, SW IV-134 alone and a combination of the two drugs. Treatment efficacy was determined using luminescent cell viability assays. Caspase-3/7,-8 and-9 activities were measured as complementary indicators of death pathway activation. Syngeneic mouse models and patient-derived xenograft (PDX) models of human ovarian cancer were studied for response to SW IV-134 and cisplatin monotherapy as well as combination therapy. Efficacy of the therapy was measured by tumor growth rate and survival as the primary readouts. Potential drug related toxicities were assessed at necropsy. Results: The combination treatment was consistently superior in multiple cell lines when compared to the single agents in vitro. The expected mechanism of tumor cell death, such as caspase activation, was confirmed using luminescent and flow cytometry-based assay systems. Combination therapy proved to be superior in both syngeneic and PDX-based murine models of ovarian cancer. Most notably, combination therapy resulted in a complete resolution of established tumors in all study animals in a patient-derived xenograft model of ovarian cancer. Conclusions: The addition of SW IV-134 in combination with cisplatin chemotherapy represents a promising treatment option that warrants further pre-clinical development and evaluation as a therapy for women with advanced ovarian cancer.

The combination of the farnesyl transferase inhibitor lonafarnib and the proteasome inhibitor bortezomib induces synergistic apoptosis in human myeloma cells that is associated with down-regulation of p-AKT

Blood ◽  
2005 ◽  
Vol 106 (13) ◽  
pp. 4322-4329 ◽  
Author(s):  
Ebenezer David ◽  
Shi-Yong Sun ◽  
Edmund K. Waller ◽  
Jing Chen ◽  
Fadlo R. Khuri ◽  
...  
Keyword(s):  
Cell Death ◽  
Combination Therapy ◽  
Cell Lines ◽  
Proteasome Inhibitor ◽  
Single Agent ◽  
Myeloma Cell ◽  
Tumor Cell Death ◽  
Down Regulation ◽  
Farnesyl Transferase ◽  
Farnesyl Transferase Inhibitor

The identification of signaling pathways critical to myeloma growth and progression has yielded an array of novel agents with clinical activity. Multiple myeloma (MM) growth is IL-6 dependent, and IL-6 is secreted in an autocrine/paracrine fashion with signaling via the Ras/Raf/mitogen-activated protein kinase (MAPK) pathway. We hypothesized that combining a Ras pathway inhibitor (lonafarnib, SCH66336) with a proteasome inhibitor (bortezomib, Velcade, PS-341) would enhance myeloma-cell killing. MM cell lines and primary human cells were used to test either single agent bortezomib, lonafarnib, or the combination on MM signaling and apoptosis. Combination therapy induced synergistic tumor-cell death in MM cell lines and primary MM plasma cells. Cell death was rapid and associated with increased caspase 3, 8, and 9 cleavage and concomitant down-regulation of p-AKT. Down-regulation of p-AKT was seen only in combination therapy and not seen with either single agent. Cells transfected with constitutively active p-AKT, wild-type AKT, or Bcl-2 continued to demonstrate synergistic cell death in response to the combination. The order of addition was critically important, supporting bortezomib followed by lonafarnib as the optimal schedule. The combination of a proteasome inhibitor and farnesyl transferase inhibitor demonstrates synergistic myeloma-cell death and warrants further preclinical and clinical studies.

scholarly journals Enhanced Antitumor Effect in Liver Cancer by Amino Acid Depletion-Induced Oxidative Stress

2021 ◽  
Vol 11 ◽  
Author(s):  
Keiichiro Okuda ◽  
Atsushi Umemura ◽  
Seita Kataoka ◽  
Kota Yano ◽  
Aya Takahashi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Liver Cancer ◽  
Combination Therapy ◽  
Cell Lines ◽  
Antitumor Effect ◽  
Xenograft Model ◽  
Expression Levels ◽  
Huh7 Cells ◽  
Hcc Cells

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. HCC cells consume large amounts of glutamine to survive, but can adapt to glutamine depletion in the presence of an exogenous asparagine. L-asparaginase (ASNase) converts glutamine and asparagine to glutamate and aspartate, respectively, and has been used to treat leukemia. Here we examined the effects of ASNase treatment on HCC cells and explored the potential impact of combining ASNase with the tyrosine kinase inhibitor lenvatinib (Len) for HCC treatment. Cell viability and death of HCC cell lines treated with either Len or ASNase alone or with Len and ASNase combined were determined. We assessed mRNA and protein expression levels of glutamine synthetase (GS) and asparagine synthetase (ASNS) by real-time quantitative PCR and immunoblotting. The antitumor effect of the combination therapy relative to Len or ASNase monotherapy was also evaluated in a xenograft tumor mouse model. ASNase treatment inhibited growth of SNU387 and SNU398 HCC cells, which have low GS and high ASNS expression levels, respectively, but did not clearly inhibit growth of the other cell lines. Len plus ASNase combination therapy synergistically inhibited proliferation and induced oxidative stress leading to cell death of some HCC cells lines. However, cell death of Huh7 cells, which express ASCT2, an important glutamine transporter for cancer cells, was not affected by the combination treatment. In a xenograft model, Len combined with ASNase significantly attenuated tumor development relative to mice treated with Len or ASNase alone. ASNase-mediated targeting of two amino acids, glutamine and asparagine, which are indispensable for HCC survival, induces oxidative stress and can be a novel cancer treatment option that exerts a synergistic effect when used in combination with Len.

scholarly journals CC12 Induces Apoptotic Cell Death and Cell Cycle Arrest in Human Glioblastoma Cell Lines and Mouse Xenograft Model

Molecules ◽  
2020 ◽  
Vol 25 (8) ◽  
pp. 1793
Author(s):  
Li-Yun Fann ◽  
Jui-Hu Shih ◽  
Jen-Ho Tseng ◽  
Hsu-Shan Huang ◽  
Sheng-Huang Hsiao
Keyword(s):  
Cell Cycle ◽  
Flow Cytometry ◽  
Cell Death ◽  
Cell Lines ◽  
Mtt Assay ◽  
Xenograft Model ◽  
Tumor Cell Death ◽  
Mouse Xenograft ◽  
Mouse Xenograft Model

Among central nervous system tumors, glioblastoma (GBM) is the most common and the most malignant type. Even under current standard treatments, the overall survival rate is still low and the recurrence rate is high. Therefore, developing novel and effective therapy is urgently needed. CC12, a synthesized small molecule, was evaluated for the potential anti-GBM effects in two GBM cell lines, U87MG and U118MG. The observations of cell morphology, MTT assay, flow cytometry-based apoptosis after CC12 treatment, were conducted. Western blot was performed for the investigation of the apoptotic mechanism. Positron emission tomography scan analysis and bioluminescent imaging assay using a mouse xenograft model were performed for the effect of CC12 in vivo. After treated by 10 μM CC12 for 24 h, both U118MG and U87MG cells showed tumor cell death. MTT assay results showed that the survival rates decreased when the CC12 concentrations or the treatment periods increased. Ki-67 expression and flow cytometry results indicated that the proliferation was inhibited in GBM cells, and G1 phase arrest was shown. The results of 7-AAD, Br-dUTP, and JC-1 staining all showed the apoptosis of GBM cells after CC12 treatment. Increased γH2AX, caspase-3, and poly (ADP-ribose) polymerase (PARP) levels meant the DNA damage, and increased Bcl2 family proteins after CC12 treatment indicated the intrinsic apoptotic pathway was involved in CC12 induced apoptosis. Furthermore, CC12 can induce the decrease of tumor prognostic marker DcR3. In vivo experiment results showed the effect of CC12 on tumor size reduction of CC12. In addition, the ability to cross the brain–blood barrier of CC12 was also confirmed. CC12 may have anti-tumor ability through the regulation of cell cycle and apoptosis in vitro and in vivo.

Anti-tumor activity of ADH-1 in vitro and in vivo in combination with paclitaxel in ovarian cancer cell lines

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 16050-16050
Author(s):  
M. Gupta ◽  
D. Barnes ◽  
J. Losos ◽  
G. Spehar ◽  
M. Bednarcik ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Combination Therapy ◽  
Tumor Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Xenograft Model ◽  
In Vitro Cytotoxicity ◽  
Anti Tumor Activity

16050 Background: ADH-1 is a novel N-cadherin (Ncad) antagonist. Ncad is a protein present on certain tumor cells and established tumor blood vessels. Its expression on tumor cells increases as they become more aggressive, invasive and metastatic, making it an important target for anti-cancer therapy. ADH-1 was well tolerated in phase I studies and demonstrated evidence of anti-tumor activity in 7 patients whose tumors expressed Ncad. Patient enrollment in two phase II single agent trials concluded at the end of 2006. We report on the anti-tumor activity of ADH-1 in combination with paclitaxel in cancer cell lines in vitro and in the A2780 (Ncad positive) ovarian xenograft model in vivo. Methods: In vitro cytotoxicity of SKOV-3 (ovarian) cells exposed to a fixed ratio of ADH-1 and paclitaxel simultaneously was evaluated by the WST-1 cell proliferation assay. In vivo anti-tumor activity of ADH-1, paclitaxel, and the combination was evaluated in the A2780 xenograft model. ADH-1 100 mg/kg was administered bid IP for 21 days and paclitaxel was administered qod IV for 5 days. Results: In vitro cytotoxicity assays evaluated for combination effects using CalcuSyn software indicated a strong synergistic effect of ADH-1 in combination with paclitaxel (CI <1). In vivo paclitaxel treatment produced a median Time to Endpoint (TTE) (tumor volume >2gm or study end at 60 day) of 32.1 days and 73% Tumor Growth Delay (TGD), compared to control (p=0.028). For the paclitaxel group, there was only one Tumor Free Survivor (TFS) and one transient Complete Responder (CR). ADH-1 produced a TTE of 16.1 and a -13% TGD (p>0.05). The combination of ADH-1 and paclitaxel produced a median TTE of 48.6 days, corresponding to 161% TGD (p<0.0016 compared to untreated controls, p<0.003 for vehicle treated, and p<0.005 compared to paclitaxel alone). The combination therapy generated durable CR in 5 animals, 1 transient CR and 2 PR. The combination therapy had similar toxicity to paclitaxel alone. Conclusions: In this ovarian cancer model, the combination of ADH-1 with paclitaxel produced a synergistic anti-tumor effect. Based in part on these encouraging pre-clinical results, a clinical program of ADH-1 in combination with chemotherapeutic agents has been initiated. No significant financial relationships to disclose.

scholarly journals Expectations and Challenges of First-Line Maintenance Therapy for Advanced Ovarian Cancer

Medicina ◽  
2021 ◽  
Vol 57 (5) ◽  
pp. 501
Author(s):  
Tadahiro Shoji ◽  
Chie Sato ◽  
Hidetoshi Tomabechi ◽  
Eriko Takatori ◽  
Yoshitaka Kaido ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Immune Checkpoint ◽  
Clinical Studies ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Advanced Ovarian Cancer ◽  
Targeted Drugs ◽  
First Line ◽  
Double Blind ◽  
Platinum Based Chemotherapy

The incidence of ovarian cancer, which has had a poor prognosis, is increasing annually. Currently, the prognosis is expected to improve with the use of molecular-targeted drugs and immune checkpoint inhibitors as maintenance therapies after the first-line chemotherapy. The GOG218 and ICON7 studies reported the usefulness of bevacizumab and the SOLO-1 and PRIMA (A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study of Niraparib Maintenance Treatment in Patients With Advanced Ovarian Cancer Following Response on Front-Line Platinum-Based Chemotherapy) studies have reported the usefulness of olaparib and niraparib, respectively. The ATHENA study investigating the usefulness of rucaparib is currently ongoing. Although clinical studies of immune checkpoint inhibitors are lagging in the field of gynecology, many clinical studies using programmed death cell-1 (PD-1) and PD-1 ligand 1 (PD-L1) antibodies are currently ongoing. Some biomarkers have been identified for molecular-targeted drugs, but none have been identified for immune checkpoint inhibitors, which is a challenge that should be addressed in the future.

scholarly journals Combination of Niraparib, Cisplatin and Twist Knockdown in Cisplatin-Resistant Ovarian Cancer Cells Potentially Enhances Synthetic Lethality through ER-Stress Mediated Mitochondrial Apoptosis Pathway

2021 ◽  
Vol 22 (8) ◽  
pp. 3916
Author(s):  
Entaz Bahar ◽  
Ji-Ye Kim ◽  
Dong-Chul Kim ◽  
Hyun-Soo Kim ◽  
Hyonok Yoon
Keyword(s):  
Ovarian Cancer ◽  
Cell Culture ◽  
Cell Death ◽  
Er Stress ◽  
Cisplatin Resistance ◽  
Cross Resistance ◽  
Ovarian Cancer Cells ◽  
Apoptosis Pathway ◽  
Platinum Based Chemotherapy

Poly (ADP-ribose) polymerase 1 inhibitors (PARPi) are used to treat recurrent ovarian cancer (OC) patients due to greater survival benefits and minimal side effects, especially in those patients with complete or partial response to platinum-based chemotherapy. However, acquired resistance of platinum-based chemotherapy leads to the limited efficacy of PARPi monotherapy in most patients. Twist is recognized as a possible oncogene and contributes to acquired cisplatin resistance in OC cells. In this study, we show how Twist knockdown cisplatin-resistant (CisR) OC cells blocked DNA damage response (DDR) to sensitize these cells to a concurrent treatment of cisplatin as a platinum-based chemotherapy agent and niraparib as a PARPi on in vitro two-dimensional (2D) and three-dimensional (3D) cell culture. To investigate the lethality of PARPi and cisplatin on Twist knockdown CisR OC cells, two CisR cell lines (OV90 and SKOV3) were established using step-wise dose escalation method. In addition, in vitro 3D spheroidal cell model was generated using modified hanging drop and hydrogel scaffolds techniques on poly-2-hydroxylethly methacrylate (poly-HEMA) coated plates. Twist expression was strongly correlated with the expression of DDR proteins, PARP1 and XRCC1 and overexpression of both proteins was associated with cisplatin resistance in OC cells. Moreover, combination of cisplatin (Cis) and niraparib (Nira) produced lethality on Twist-knockdown CisR OC cells, according to combination index (CI). We found that Cis alone, Nira alone, or a combination of Cis+Nira therapy increased cell death by suppressing DDR proteins in 2D monolayer cell culture. Notably, the combination of Nira and Cis was considerably effective against 3D-cultures of Twist knockdown CisR OC cells in which Endoplasmic reticulum (ER) stress is upregulated, leading to initiation of mitochondrial-mediated cell death. In addition, immunohistochemically, Cis alone, Nira alone or Cis+Nira showed lower ki-67 (cell proliferative marker) expression and higher cleaved caspase-3 (apoptotic marker) immuno-reactivity. Hence, lethality of PARPi with the combination of Cis on Twist knockdown CisR OC cells may provide an effective way to expand the therapeutic potential to overcome platinum-based chemotherapy resistance and PARPi cross resistance in OC.

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