scholarly journals Targeting Autophagy by MPT0L145, a Highly Potent PIK3C3 Inhibitor, Provides Synergistic Interaction to Targeted or Chemotherapeutic Agents in Cancer Cells

Cancers ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 1345 ◽  
Author(s):  
Chun-Han Chen ◽  
Tsung-Han Hsieh ◽  
Yu-Chen Lin ◽  
Yun-Ru Liu ◽  
Jing-Ping Liou ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Drug Combination ◽  
Therapeutic Potential ◽  
Synthetic Lethality ◽  
Apoptotic Cell ◽  
A549 Cells ◽  
Growth Factor Receptor ◽  
Chemotherapeutic Agents ◽  
Autophagic Flux ◽  
Combination Strategies

Anticancer therapies reportedly promote pro-survival autophagy in cancer cells that confers drug resistance, rationalizing the concept to combine autophagy inhibitors to increase their therapeutic potential. We previously identified that MPT0L145 is a PIK3C3/FGFR inhibitor that not only increases autophagosome formation due to fibroblast growth factor receptor (FGFR) inhibition but also perturbs autophagic flux via PIK3C3 inhibition in bladder cancer cells harboring FGFR activation. In this study, we hypothesized that combined-use of MPT0L145 with agents that induce pro-survival autophagy may provide synthetic lethality in cancer cells without FGFR activation. The results showed that MPT0L145 synergistically sensitizes anticancer effects of gefitinib and gemcitabine in non-small cell lung cancer A549 cells and pancreatic cancer PANC-1 cells, respectively. Mechanistically, drug combination increased incomplete autophagy due to impaired PIK3C3 function by MPT0L145 as evidenced by p62 accumulation and no additional apoptotic cell death was observed. Meanwhile, drug combination perturbed survival pathways and increased vacuolization and ROS production in cancer cells. In conclusion, the data suggest that halting pro-survival autophagy by targeting PIK3C3 with MPT0L145 significantly sensitizes cancer cells to targeted or chemotherapeutic agents, fostering rational combination strategies for cancer therapy in the future.

scholarly journals Quinacrine-Induced Autophagy in Ovarian Cancer Triggers Cathepsin-L Mediated Lysosomal/Mitochondrial Membrane Permeabilization and Cell Death

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2004
Author(s):  
Prabhu Thirusangu ◽  
Christopher L. Pathoulas ◽  
Upasana Ray ◽  
Yinan Xiao ◽  
Julie Staub ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Death ◽  
Cytochrome C ◽  
Cancer Cells ◽  
Apoptotic Cell ◽  
Cathepsin L ◽  
Membrane Permeabilization ◽  
Apoptotic Cell Death ◽  
Ovarian Cancer Cells ◽  
Autophagic Flux

We previously reported that the antimalarial compound quinacrine (QC) induces autophagy in ovarian cancer cells. In the current study, we uncovered that QC significantly upregulates cathepsin L (CTSL) but not cathepsin B and D levels, implicating the specific role of CTSL in promoting QC-induced autophagic flux and apoptotic cell death in OC cells. Using a Magic Red® cathepsin L activity assay and LysoTracker red, we discerned that QC-induced CTSL activation promotes lysosomal membrane permeability (LMP) resulting in the release of active CTSL into the cytosol to promote apoptotic cell death. We found that QC-induced LMP and CTSL activation promotes Bid cleavage, mitochondrial outer membrane permeabilization (MOMP), and mitochondrial cytochrome-c release. Genetic (shRNA) and pharmacological (Z-FY(tBU)-DMK) inhibition of CTSL markedly reduces QC-induced autophagy, LMP, MOMP, apoptosis, and cell death; whereas induced overexpression of CTSL in ovarian cancer cell lines has an opposite effect. Using recombinant CTSL, we identified p62/SQSTM1 as a novel substrate of CTSL, suggesting that CTSL promotes QC-induced autophagic flux. CTSL activation is specific to QC-induced autophagy since no CTSL activation is seen in ATG5 knockout cells or with the anti-malarial autophagy-inhibiting drug chloroquine. Importantly, we showed that upregulation of CTSL in QC-treated HeyA8MDR xenografts corresponds with attenuation of p62, upregulation of LC3BII, cytochrome-c, tBid, cleaved PARP, and caspase3. Taken together, the data suggest that QC-induced autophagy and CTSL upregulation promote a positive feedback loop leading to excessive autophagic flux, LMP, and MOMP to promote QC-induced cell death in ovarian cancer cells.

scholarly journals Enhanced antineoplastic/therapeutic efficacy using 5-fluorouracil-loaded calcium phosphate nanoparticles

2018 ◽  
Vol 9 ◽  
pp. 2499-2515 ◽  
Author(s):  
Shanid Mohiyuddin ◽  
Saba Naqvi ◽  
Gopinath Packirisamy
Keyword(s):  
Electron Microscopy ◽  
Calcium Phosphate ◽  
Cancer Cells ◽  
Therapeutic Efficacy ◽  
Therapeutic Potential ◽  
Physicochemical Characterization ◽  
A549 Cells ◽  
Dependent Manner ◽  
Calcium Phosphate Nanoparticles ◽  
Apoptotic Induction

In the past few decades, the successful theranostic application of nanomaterials in drug delivery systems has significantly improved the antineoplastic potency of conventional anticancer therapy. Several mechanistic advantages of nanomaterials, such as enhanced permeability, retention, and low toxicity, as well as surface engineering with targeting moieties, can be used as a tool in enhancing the therapeutic efficacy of current approaches. Inorganic calcium phosphate nanoparticles have the potential to increase the therapeutic potential of antiproliferative drugs due to their excellent loading efficiency, biodegradable nature and controlled-release behaviour. Herein, we report a novel system of 5-fluorouracil (5-FU)-loaded calcium phosphate nanoparticles (CaP@5-FU NPs) synthesized via a reverse micelle method. The formation of monodispersed, spherical, crystalline nanoparticles with an approximate diameter of 160–180 nm was confirmed by different methods. The physicochemical characterization of the synthesized CaP@5-FU NPs was done with transmission electron microscopy (TEM), dynamic light scattering (DLS), field emission scanning electron microscopy (FE-SEM), Fourier-transform infrared spectroscopy (FTIR), and X-ray diffraction (XRD). The antineoplastic potential of the CaP@5-FU NPs against colorectal and lung cancer cells was reported. The CaP@5-FU NPs were found to inhibit half the population (IC50) of lung adenocarcinoma (A549) cells at 32 μg/mL and colorectal (HCT-15) cancer cells at 48.5 μg/mL treatment. The apoptotic induction of CaP@5-FU NPs was confirmed with acridine orange/ethidium bromide (AO/EB) staining and by examining the morphological changes with Hoechst and rhodamine B staining in a time-dependent manner. The apparent membrane bleb formation was observed in FE-SEM micrographs. The up-regulated proapoptotic and down-regulated antiapoptotic gene expressions were further confirmed with semiquantitative reverse transcriptase polymerase chain reaction (PCR). The increased intracellular reactive oxygen species (ROS) were quantified via flow cytometry upon CaP@5-FU NP treatment. Likewise, the cell cycle analysis was performed to confirm the enhanced apoptotic induction. Our study concludes that the calcium phosphate nanocarriers system, i.e. CaP@5-FU NPs, has higher antineoplastic potential as compared to 5-FU alone and can be used as an improved alternative to the antimitotic drug, which causes severe side effects when administrated alone.

Mechanism of Cepharanthine Cytotoxicity in Human Ovarian Cancer Cells

Planta Medica ◽  
2018 ◽  
Vol 85 (01) ◽  
pp. 41-47 ◽  
Author(s):  
Vilawan Payon ◽  
Chanaporn Kongsaden ◽  
Wannarasmi Ketchart ◽  
Apiwat Mutirangura ◽  
Piyanuch Wonganan
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Ovarian Cancer Cell ◽  
Apoptotic Cell ◽  
Chemotherapeutic Agents ◽  
Ovarian Cancer Cells ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Ovarian Cancer Cell Lines ◽  
Underlying Mechanisms

AbstractCepharanthine (CEP), a medicinal product derived from Stephania cephalantha Hayata, possesses a potent cytotoxicity against several types of cancers. Recently, we have found that CEP could efficiently inhibit the growth of mutated p53 colon cancer cells, which are often resistant to commonly used chemotherapeutic agents. In this study, we evaluated the cytotoxic effect and the underlying mechanisms of CEP on both chemosensitive CaOV-3 and chemoresistant OVCAR-3 ovarian cancer cell lines. The present study demonstrated that CEP significantly inhibited the growth of CaOV-3 and OVCAR-3 cells in a time- and concentration-dependent manner. CEP arrested CaOV-3 and OVCAR-3 cells in the G1 phase and S phase of cell cycle, respectively. Western blot analysis demonstrated that CEP markedly increased the expression of p21Waf1 protein and decreased the expression of cyclins A and D proteins in both CaOV-3 and OVCAR-3 cells. Additionally, CEP triggered apoptotic cell death in OVCAR-3 cells. Taken together, the above results suggest that CEP is a promising anticancer drug for ovarian cancer.

Extract from the Leaves of Toona sinensis Roemor Exerts Potent Antiproliferative Effect on Human Lung Cancer Cells

2002 ◽  
Vol 30 (02n03) ◽  
pp. 307-314 ◽  
Author(s):  
Hui-Chiu Chang ◽  
Wen-Chun Hung ◽  
Ming-Shyan Huang ◽  
Hseng-Kuang Hsu
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Human Lung ◽  
Apoptotic Cell ◽  
A549 Cells ◽  
Lung Cancer Cells ◽  
Lung Fibroblasts ◽  
Human Lung Cancer ◽  
Toona Sinensis

Recent study indicated that the components of Toona sinensis Roemor have potent anti-inflammatory and analgesic effects. These components have also been reported to inhibit the growth of boils in vivo. In this study, we investigated the effect of crude extract from the leaves of Toona sinensis Roemor on the proliferation of A549 lung cancer cells. We found that the extract effectively blocked cell cycle progression by inhibiting the expression of cyclin D1 and E in A549 cells. Additionally, incubation of the extract led to activation of caspase-3-like proteases and apoptotic cell death. Conversely, the extract did not show any significant cytotoxic effect on primarily cultured human foreskin fibroblasts or MRC-5 human lung fibroblasts. Therefore, antiproliferative action of the extract is specific for tumor cells. Our results suggest that the components of Toona sinensis Roemor have potent anticancer effects in vitro and identification of the useful components in the extract may lead to the development of a novel class of anticancer drugs.

scholarly journals Syrosingopine sensitizes cancer cells to killing by metformin

2016 ◽  
Vol 2 (12) ◽  
pp. e1601756 ◽  
Author(s):  
Don Benjamin ◽  
Marco Colombi ◽  
Sravanth K. Hindupur ◽  
Charles Betz ◽  
Heidi A. Lane ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Drug Combination ◽  
Therapeutic Strategy ◽  
Synthetic Lethality ◽  
Glycolytic Enzyme ◽  
Transformed Cells ◽  
Monoamine Transporters ◽  
Vesicular Monoamine Transporters ◽  
The Individual

We report that the anticancer activity of the widely used diabetic drug metformin is strongly potentiated by syrosingopine. Synthetic lethality elicited by combining the two drugs is synergistic and specific to transformed cells. This effect is unrelated to syrosingopine’s known role as an inhibitor of the vesicular monoamine transporters. Syrosingopine binds to the glycolytic enzyme α-enolase in vitro, and the expression of the γ-enolase isoform correlates with nonresponsiveness to the drug combination. Syrosingopine sensitized cancer cells to metformin and its more potent derivative phenformin far below the individual toxic threshold of each compound. Thus, combining syrosingopine and codrugs is a promising therapeutic strategy for clinical application for the treatment of cancer.

scholarly journals Epidermal Growth Factor Receptor: Key to Selective Intracellular Delivery

2020 ◽  
Vol 85 (9) ◽  
pp. 967-993 ◽  
Author(s):  
A. A. Rosenkranz ◽  
T. A. Slastnikova
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Cancer Cells ◽  
Targeted Delivery ◽  
Growth Factor Receptor ◽  
Chemotherapeutic Agents ◽  
Egfr Signaling Pathway ◽  
Egfr Activation ◽  
Epidermal Growth

Abstract Epidermal growth factor receptor (EGFR) is an integral surface protein mediating cellular response to a number of growth factors. Its overexpression and increased activation due to mutations is one of the most common traits of many types of cancer. Development and clinical use of the agents, which block EGFR activation, became a prime example of the personalized targeted medicine. However, despite the obvious success in this area, cancer cure remains unattainable in most cases. Because of that, as well as the result of the search for possible ways to overcome the difficulties of treatment, a huge number of new treatment methods relying on the use of EGFR overexpression and its changes to destroy cancer cells. Modern data on the structure, functioning, and intracellular transport of EGFR, its natural ligands, as well as signaling cascades triggered by the EGFR activation, peculiarities of the EGFR expression and activation in oncological disorders, as well as applied therapeutic approaches aimed at blocking EGFR signaling pathway are summarized and analyzed in this review. Approaches to the targeted delivery of various chemotherapeutic agents, radionuclides, immunotoxins, photosensitizers, as well as the prospects for gene therapy aimed at cancer cells with EGFR overexpression are reviewed in detail. It should be noted that increasing attention is being paid nowadays to the development of multifunctional systems, either carrying several different active agents, or possessing several environment-dependent transport functions. Potentials of the systems based on receptor-mediated endocytosis of EGFR and their possible advantages and limitations are discussed.

scholarly journals Alternate therapeutic pathways for PARP inhibitors and potential mechanisms of resistance

2021 ◽  
Vol 53 (1) ◽  
pp. 42-51
Author(s):  
Dae-Seok Kim ◽  
Cristel V. Camacho ◽  
W. Lee Kraus
Keyword(s):  
Clinical Trials ◽  
Homologous Recombination ◽  
Cancer Cells ◽  
Synthetic Lethality ◽  
Parp Inhibitor ◽  
Cancer Therapeutics ◽  
Progression Free Survival ◽  
Parp Inhibitors ◽  
Parp Inhibition ◽  
Combination Strategies

AbstractHomologous recombination (HR) repair deficiency impairs the proper maintenance of genomic stability, thus rendering cancer cells vulnerable to loss or inhibition of DNA repair proteins, such as poly(ADP-ribose) polymerase-1 (PARP-1). Inhibitors of nuclear PARPs are effective therapeutics for a number of different types of cancers. Here we review key concepts and current progress on the therapeutic use of PARP inhibitors (PARPi). PARPi selectively induce synthetic lethality in cancer cells with homologous recombination deficiencies (HRDs), the most notable being cancer cells harboring mutations in the BRCA1 and BRCA2 genes. Recent clinical evidence, however, shows that PARPi can be effective as cancer therapeutics regardless of BRCA1/2 or HRD status, suggesting that a broader population of patients might benefit from PARPi therapy. Currently, four PARPi have been approved by the Food and Drug Administration (FDA) for the treatment of advanced ovarian and breast cancer with deleterious BRCA mutations. Although PARPi have been shown to improve progression-free survival, cancer cells inevitably develop resistance, which poses a significant obstacle to the prolonged use of PARP inhibitors. For example, somatic BRCA1/2 reversion mutations are often identified in patients with BRCA1/2-mutated cancers after treatment with platinum-based therapy, causing restoration of HR capacity and thus conferring PARPi resistance. Accordingly, PARPi have been studied in combination with other targeted therapies to overcome PARPi resistance, enhance PARPi efficacy, and sensitize tumors to PARP inhibition. Moreover, multiple clinical trials are now actively underway to evaluate novel combinations of PARPi with other anticancer therapies for the treatment of PARPi-resistant cancer. In this review, we highlight the mechanisms of action of PARP inhibitors with or without BRCA1/2 defects and provide an overview of the ongoing clinical trials of PARPi. We also review the current progress on PARPi-based combination strategies and PARP inhibitor resistance.

scholarly journals Inhibition of DNA2 nuclease as a therapeutic strategy targeting replication stress in cancer cells

2017 ◽  
Author(s):  
Sandeep Kumar ◽  
Xiangdong Peng ◽  
James M. Daley ◽  
Lin Yang ◽  
Jianfeng Shen ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Therapeutic Potential ◽  
Synthetic Lethality ◽  
Replication Stress ◽  
Nuclease Activity ◽  
Dna Breaks ◽  
Repair Capacity ◽  
Genetic Ablation ◽  
Associated Lesions ◽  
Dna End Resection

AbstractReplication stress is a characteristic feature of cancer cells, which is resulted from sustained proliferative signaling induced by activation of oncogenes or loss of tumor suppressors. In cancer cells, oncogene-induced replication stress manifests as replication-associated lesions, predominantly double-strand DNA breaks (DSBs). An essential mechanism utilized by cells to repair replication-associated DSBs is homologous recombination (HR). In order to overcome replication stress and survive, cancer cells often require enhanced HR repair capacity. Therefore, the key link between HR repair and cellular tolerance to replication-associated DSBs provides us with a mechanistic rationale for exploiting synthetic lethality between HR repair inhibition and replication stress. Our studies showed that DNA2 nuclease is an evolutionarily conserved essential component of HR repair machinery. Here we demonstrate that DNA2 is indeed overexpressed in pancreatic cancers, one of the deadliest and more aggressive forms of human cancers, where mutations in the KRAS are present in 90%-95% of cases. In addition, depletion of DNA2 significantly reduces pancreatic cancer cell survival and xenograft tumor growth, suggesting the therapeutic potential of DNA2 inhibition. Finally, we develop a robust high-throughput biochemistry assay to screen for inhibitors of the DNA2 nuclease activity. The top inhibitors were shown to be efficacious against both yeast Dna2 and human DNA2. Treatment of cancer cells with DNA2 inhibitors recapitulates phenotypes observed upon DNA2 depletion, including decreased DNA end resection and attenuation of HR repair. Similar to genetic ablation of DNA2, chemical inhibition of DNA2 selectively attenuates the growth of various cancer cells with oncogene-induced replication stress. Taken together, our findings open a new avenue to develop a new class of anti-cancer drugs by targeting druggable nuclease DNA2. We 4, 16. In propose DNA2 inhibition as new strategy in cancer therapy by targeting replication stress, a molecular property of cancer cells that is acquired as a result of oncogene activation instead of targeting undruggable oncoprotein itself such as KRAS.

scholarly journals Ilimaquinone Induces the Apoptotic Cell Death of Cancer Cells by Reducing Pyruvate Dehydrogenase Kinase 1 Activity

2020 ◽  
Vol 21 (17) ◽  
pp. 6021 ◽  
Author(s):  
Choong-Hwan Kwak ◽  
Ling Jin ◽  
Jung Ho Han ◽  
Chang Woo Han ◽  
Eonmi Kim ◽  
...  
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Pyruvate Dehydrogenase ◽  
Apoptotic Cell ◽  
Aerobic Glycolysis ◽  
Computational Simulation ◽  
A549 Cells ◽  
Apoptotic Cell Death ◽  
Pyruvate Dehydrogenase Kinase ◽  
Pyruvate Dehydrogenase Kinase 1

In cancer cells, aerobic glycolysis rather than oxidative phosphorylation (OxPhos) is generally preferred for the production of ATP. In many cancers, highly expressed pyruvate dehydrogenase kinase 1 (PDK1) reduces the activity of pyruvate dehydrogenase (PDH) by inducing the phosphorylation of its E1α subunit (PDHA1) and subsequently, shifts the energy metabolism from OxPhos to aerobic glycolysis. Thus, PDK1 has been regarded as a target for anticancer treatment. Here, we report that ilimaquinone (IQ), a sesquiterpene quinone isolated from the marine sponge Smenospongia cerebriformis, might be a novel PDK1 inhibitor. IQ decreased the cell viability of human and murine cancer cells, such as A549, DLD-1, RKO, and LLC cells. The phosphorylation of PDHA1, the substrate of PDK1, was reduced by IQ in the A549 cells. IQ decreased the levels of secretory lactate and increased oxygen consumption. The anticancer effect of IQ was markedly reduced in PDHA1-knockout cells. Computational simulation and biochemical assay revealed that IQ interfered with the ATP binding pocket of PDK1 without affecting the interaction of PDK1 and the E2 subunit of the PDH complex. In addition, similar to other pyruvate dehydrogenase kinase inhibitors, IQ induced the generation of mitochondrial reactive oxygen species (ROS) and depolarized the mitochondrial membrane potential in the A549 cells. The apoptotic cell death induced by IQ treatment was rescued in the presence of MitoTEMPO, a mitochondrial ROS inhibitor. In conclusion, we suggest that IQ might be a novel candidate for anticancer therapeutics that act via the inhibition of PDK1 activity.

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