-
Journal of Nanobiotechnology May 2022By hindering energy supply pathway for cancer cells, an alternative therapeutic strategy modality is put forward: tumor starvation therapy. And yet only in this blockade...
Boosting nutrient starvation-dominated cancer therapy through curcumin-augmented mitochondrial Ca overload and obatoclax-mediated autophagy inhibition as supported by a novel nano-modulator GO-Alg@CaP/CO.
BACKGROUND
By hindering energy supply pathway for cancer cells, an alternative therapeutic strategy modality is put forward: tumor starvation therapy. And yet only in this blockade of glucose supply which is far from enough to result in sheer apoptosis of cancer cells.
RESULTS
In an effort to boost nutrient starvation-dominated cancer therapy, here a novel mitochondrial Ca modulator Alg@CaP were tailor-made for the immobilization of Glucose oxidase for depriving the intra-tumoral glucose, followed by the loading of Curcumin to augment mitochondrial Ca overload to maximize the therapeutic efficiency of cancer starvation therapy via mitochondrial dysfunctions. Also, autophagy inhibitors Obatoclax were synchronously incorporated in this nano-modulator to highlight autophagy inhibition.
CONCLUSION
Here, a promising complementary modality for the trebling additive efficacy of starvation therapy was described for cutting off the existing energy sources in starvation therapy through Curcumin-augmented mitochondrial Ca overload and Obatoclax-mediated autophagy inhibition.
Topics: Apoptosis; Autophagy; Cell Line, Tumor; Curcumin; Glucose; Humans; Indoles; Neoplasms; Nutrients; Pyrroles; Starvation
PubMed: 35551609
DOI: 10.1186/s12951-022-01439-0 -
BMC Cancer Oct 2019Neuroblastoma (NB) is a frequent pediatric tumor associated with poor prognosis. The disregulation of Bcl-2, an anti-apoptotic protein, is crucial for the tumoral...
BACKGROUND
Neuroblastoma (NB) is a frequent pediatric tumor associated with poor prognosis. The disregulation of Bcl-2, an anti-apoptotic protein, is crucial for the tumoral development and chemoresistance. Autophagy is also implicated in tumor cell survival and chemoresistance. The aim of our study was to demonstrate therapeutic efficiency of GX 15-070, a pan-Bcl-2 family inhibitor, used alone and in combination with conventional drugs or with hydroxychloroquine (HCQ), an autophagy inhibitor.
METHODS
Five neuroblastoma cell lines were tested for the cytotoxic activity of GX 15-070 alone or in combination with cisplatin, doxorubicin, HCQ or Z-VAD-FMK a broad-spectrum caspase inhibitor. Apoptosis and autophagy levels were studied by western-blot and FACS. Orthotopic injections were performed on NOD/LtSz-scid/IL-2Rgamma null mice that were treated with either GX 15-070 alone or in combination with HCQ.
RESULTS
Synergistic cytotoxicity was observed for the drug combination in all of the 5 neuroblastoma cell lines tested, including MYCN amplified lines and in cancer stem cells. GX 15-070 significantly increased apoptosis and autophagy in neuroblastoma cells as evidenced by increased levels of the autophagy marker, LC3-II. Inhibition of autophagy by HCQ, further increased the cytotoxicity of this combinatorial treatment, suggesting that autophagy induced by these agent plays a cytoprotective role. In vivo, GX 15-070 combined with HCQ significantly decreased the growth of the tumor and the number of distant metastases.
CONCLUSIONS
Based on the synergistic effect of HCQ and GX 15-070 observed in this study, the combination of these two drugs may be utilized as a new therapeutic approach for neuroblastoma.
Topics: Adrenal Gland Neoplasms; Animals; Antineoplastic Agents; Apoptosis; Autophagy; Cell Line, Tumor; Cell Survival; Drug Resistance, Neoplasm; Drug Synergism; Female; Humans; Hydroxychloroquine; Indoles; Male; Mice; Mice, Inbred NOD; Mice, SCID; Neuroblastoma; Proto-Oncogene Proteins c-bcl-2; Pyrroles; Tumor Burden; Xenograft Model Antitumor Assays
PubMed: 31664947
DOI: 10.1186/s12885-019-6195-y -
Biomaterials Feb 2020Wnt/β-catenin signaling cascade is highly associated with tumorigenesis and progression of various cancers. Targeting Wnt/β-catenin signaling exhibits a promising way...
Wnt/β-catenin signaling cascade is highly associated with tumorigenesis and progression of various cancers. Targeting Wnt/β-catenin signaling exhibits a promising way for cancer treatment. Herein, dual-stimuli responsive nanotheranostics was synthesized, which was composed of melanin coated magnetic nanoparticles (MMNs) and Wnt signaling inhibitor obatoclax (OBX) for multimodality imaging guided mild hyperthermia-enhanced chemotherapy. The MMNs could be used as contrast agents for magnetic resonance imaging (MRI) and photoacoustic imaging (PAI) guided photothermal therapy. In addition, OBX-loaded MMNs (OBX-MMNs) were specific response to both pH changes and near-infrared (NIR) light illumination, which could trigger OBX release. Most intriguingly, tumor tissue accumulation and cellular internalization of this nanotheranostics could be dramatically enhanced through mild hyperthermia generated by laser-irradiated MMNs. Laser irradiation exhibited efficient chemotherapeutic outcome through enhancing OBX-mediated inhibition of the Wnt/β-catenin signaling. Our results indicated the as-prepared OBX-MMNs hold great potential for MR/PA dual-modal imaging guided mild hyperthermia-enhanced chemotherapy.
Topics: Cell Line, Tumor; Doxorubicin; Humans; Hyperthermia; Hyperthermia, Induced; Nanoparticles; Phototherapy; Theranostic Nanomedicine; Wnt Signaling Pathway; beta Catenin
PubMed: 31896513
DOI: 10.1016/j.biomaterials.2019.119709 -
Cancer Letters Aug 2015Activation of hypoxia-inducible factor (HIF)-1 is a feature of hypoxic solid tumors that has been associated with drug resistance, mainly due to disruption of Bcl-2...
Activation of hypoxia-inducible factor (HIF)-1 is a feature of hypoxic solid tumors that has been associated with drug resistance, mainly due to disruption of Bcl-2 family dynamics. Resetting the balance in favor of proapoptotic family members is an attractive therapeutic goal that has been pursued by developing BH3-mimetic compounds. In the present study we evaluated the response of human colon adenocarcinoma cells to the BH3-mimetic obatoclax (OBX), in terms of growth arrest, apoptosis and autophagy, in the presence or absence of HIF-1α-stabilizing conditions; its possible effect on HIF-1α expression and HIF-1 activity; and the possibility to improve the response of colon cancer cells to cytotoxic chemotherapeutics by combining them with OBX. Colon cancer cell response to the BH3-mimetic was unmodified by HIF-1 activation and OBX induced a decrease in HIF-1α protein levels and HIF-1 transcriptional activity, probably by decreasing HIF-1α synthesis and facilitating a VHL-independent proteasomal degradation pathway. Finally, a chemosensitizing effect of OBX with respect to 5-fluorouracil or oxaliplatin treatment was observed, highlighting the possibility that patients with hypoxic colon tumors might benefit from combined regimens including OBX.
Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Hypoxia; Cell Proliferation; Colonic Neoplasms; Down-Regulation; Drug Synergism; Fluorouracil; HCT116 Cells; HT29 Cells; Humans; Hypoxia-Inducible Factor 1; Hypoxia-Inducible Factor 1, alpha Subunit; Indoles; Pyrroles; Transcriptional Activation
PubMed: 25979228
DOI: 10.1016/j.canlet.2015.05.008 -
Electrophoresis Aug 2017Inherent electrical properties of cells can be beneficial to characterize different cell lines and their response to experimental drugs. This paper presents a novel...
Inherent electrical properties of cells can be beneficial to characterize different cell lines and their response to experimental drugs. This paper presents a novel method to characterize the response of breast cancer cells to drug stimuli through use of off-chip passivated-electrode insulator-based dielectrophoresis (OπDEP) and the application of AC electric fields. This work is the first to demonstrate the ability of OπDEP to differentiate between two closely related breast cancer cell lines, LCC1 and LCC9 while assessing their drug sensitivity to an experimental anti-cancer agent, Obatoclax. Although both cell lines are derivatives of estrogen-responsive MCF-7 breast cancer cells, growth of LCC1 is estrogen independent and anti-estrogen responsive, while LCC9 is both estrogen-independent and anti-estrogen resistant. Under the same operating conditions, LCC1 and LCC9 had different DEP profiles. LCC1 cells had a trapping onset (crossover) frequency of 700 kHz and trapping efficiencies between 30-40%, while LCC9 cells had a lower crossover frequency (100 kHz) and showed higher trapping efficiencies of 40-60%. When exposed to the Obatoclax, both cell lines exhibited dose-dependent shifts in DEP crossover frequency and trapping efficiency. Here, DEP results supplemented with cell morphology and proliferation assays help us to understand the response of these breast cancer cells to Obatoclax.
Topics: Antineoplastic Agents; Breast Neoplasms; Cell Proliferation; Cell Size; Drug Resistance, Neoplasm; Electrodes; Electrophoresis; Estrogen Antagonists; Female; Humans; Indoles; MCF-7 Cells; Microfluidic Analytical Techniques; Pyrroles
PubMed: 28608427
DOI: 10.1002/elps.201600447 -
Heliyon Apr 2023Phenotypic plasticity (PP) is a major promoter of tumor metastasis and drug resistance. Nevertheless, the molecular features and clinical significance of phenotypic...
BACKGROUND
Phenotypic plasticity (PP) is a major promoter of tumor metastasis and drug resistance. Nevertheless, the molecular features and clinical significance of phenotypic plasticity in lung squamous cell carcinomas (LSCC) remained largely unexplored.
METHODS
Phenotypic plasticity-related genes (PPRG) and clinical information of LSCC were downloaded from the cancer genome atlas (TCGA). The expression profiles of PPRG were compared between patients with and without lymph node metastasis. The prognostic signature was constructed, and survival analysis was performed based on phenotypic plasticity. Immunotherapy responses, chemotherapeutic drugs and targeted drug responses were investigated. In addition, the results were verified in an external cohort.
RESULTS
Patients with and without lymph node metastasis exhibited significantly different genomic characteristics of phenotypic plasticity. Enrichment analysis showed that PP was strongly associated with cell responses and cell contraction. Survival analysis demonstrated that PPRG could serve as independent prognostic factor for overall survival. The phenotypic plasticity-related signature successfully divided patients into high- and low-PP score groups. Patients with low-PP scores were more sensitive to PD-L1, Cisplatin, Gefitinib, Obatoclax. Mesylate, Paclitaxel, Sorafenib and Vinorelbine (all p < 0.05). While, patients with low-PP scores were more sensitive to Axitinib and Camptothecin (all p < 0.05). Consistent with the results from TCGA, the external cohort validated the above findings.
CONCLUSIONS
Our study revealed that phenotypic plasticity may be involved in the lymph node metastasis in LSCC through regulating cell responses and cell contraction. Evaluation of phenotypic plasticity will assist clinicians in making treatment strategies.
PubMed: 37025908
DOI: 10.1016/j.heliyon.2023.e14614 -
Nucleic Acids Research Feb 2015We define a new category of candidate tumor drivers in cancer genome evolution: 'selected expression regulators' (SERs)-genes driving dysregulated transcriptional...
We define a new category of candidate tumor drivers in cancer genome evolution: 'selected expression regulators' (SERs)-genes driving dysregulated transcriptional programs in cancer evolution. The SERs are identified from genome-wide tumor expression data with a novel method, namely SPARROW ( SPAR: se selected exp R: essi O: n regulators identified W: ith penalized regression). SPARROW uncovers a previously unknown connection between cancer expression variation and driver events, by using a novel sparse regression technique. Our results indicate that SPARROW is a powerful complementary approach to identify candidate genes containing driver events that are hard to detect from sequence data, due to a large number of passenger mutations and lack of comprehensive sequence information from a sufficiently large number of samples. SERs identified by SPARROW reveal known driver mutations in multiple human cancers, along with known cancer-associated processes and survival-associated genes, better than popular methods for inferring gene expression networks. We demonstrate that when applied to acute myeloid leukemia expression data, SPARROW identifies an apoptotic biomarker (PYCARD) for an investigational drug obatoclax. The PYCARD and obatoclax association is validated in 30 AML patient samples.
Topics: Brain Neoplasms; Gene Expression Profiling; Gene Regulatory Networks; Glioblastoma; Humans; Leukemia, Myeloid, Acute; Mutation
PubMed: 25583238
DOI: 10.1093/nar/gku1290 -
Antioxidants (Basel, Switzerland) Oct 2018Pulmonary arterial hypertension (PAH) is a fatal disease without satisfactory therapeutic options. By the time patients are diagnosed with this disease, the remodeling...
Pulmonary arterial hypertension (PAH) is a fatal disease without satisfactory therapeutic options. By the time patients are diagnosed with this disease, the remodeling of pulmonary arteries has already developed due to the abnormal growth of pulmonary vascular cells. Therefore, agents that reduce excess pulmonary vascular cells have therapeutic potential. Bcl-2 is known to function in an antioxidant pathway to prevent apoptosis. The present study examined the effects of inhibitors of the anti-apoptotic proteins Bcl-2 and Bcl-x. ABT-263 (Navitoclax), ABT-199 (Venetoclax), ABT-737, and Obatoclax, which all promoted the death of cultured human pulmonary artery smooth muscle cells. Further examinations using ABT-263 showed that Bcl-2/Bcl-x inhibition indeed promoted apoptotic programmed cell death. ABT-263-induced cell death was inhibited by antioxidants. ABT-263 also promoted autophagy; however, the inhibition of autophagy did not suppress ABT-263-induced cell death. This is in contrast to other previously studied drugs, including anthracyclines and proteasome inhibitors, which were found to mediate autophagy to induce cell death. The administration of ABT-263 to rats with PAH in vivo resulted in the reversal of pulmonary vascular remodeling. Thus, promoting apoptosis by inhibiting anti-apoptotic Bcl-2 and Bcl-x effectively kills pulmonary vascular smooth muscle cells and reverses pulmonary vascular remodeling.
PubMed: 30373097
DOI: 10.3390/antiox7110150 -
Oncotarget May 2017Drug combination therapies remain pivotal for the treatment of heterogeneous malignancies, such as glioblastomas. Here, we show a novel lethal interaction between Bcl-xL...
Drug combination therapies remain pivotal for the treatment of heterogeneous malignancies, such as glioblastomas. Here, we show a novel lethal interaction between Bcl-xL and c-myc inhibition accomplished by bromodomain protein inhibitors. Established, patient-derived xenograft and stem cell-like glioma cells were treated with the novel bromodomain protein inhibitors, JQ1 and OTX015, along with BH3-mimetics, ABT263 or Obatoclax. Synergy was assessed by calculation of CI values. Small interfering RNAs (siRNAs) were used for gene silencing and mechanistic studies. In vivo experiments were performed in a glioblastoma xenograft model. Single treatments with JQ1 and OTX015 had only moderate effects on the reduction of cellular viability. However, the combination treatment of BH3-mimetics along with JQ1 or OTX015 resulted in a highly synergistic reduction of cellular viability in a broad range of different model systems of malignant glioma. Similarly, knockdown of c-myc sensitized glioma cells for ABT263 mediated cell death. The enhanced loss of cellular viability in the combination treatment was mediated by activation of apoptosis with dissipation of mitochondrial membrane potential and caspase cleavage. The combination treatment led to a modulation of anti- and pro-apoptotic Bcl-2 family members with an increase in pro-apoptotic Noxa mediated by ATF4. Small interfering RNA mediated knockdown of Bak and Noxa protected glioma cells from ABT263/JQ1 mediated apoptosis. Finally, the combination treatment of ABT263 and OTX015 resulted in a regression of tumors and a significantly smaller tumor size as compared to single or vehicle treated tumors. Thus, these results warrant clinical testing for the drug combination of BH3-mimetics along with bromodain protein inhibitors.
Topics: Acetanilides; Aniline Compounds; Animals; Antineoplastic Agents; Apoptosis; Azepines; Bcl-2-Like Protein 11; Caspases; Cell Line, Tumor; Cell Survival; Disease Models, Animal; Drug Synergism; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Glioma; Heterocyclic Compounds, 3-Ring; Humans; Membrane Potential, Mitochondrial; Mice; Proteins; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins c-myc; RNA, Small Interfering; Sulfonamides; Triazoles; Xenograft Model Antitumor Assays
PubMed: 28418907
DOI: 10.18632/oncotarget.16365 -
Current Opinion in Pharmacology Aug 2015Bcl-2 proteins are key determinants in the life-death balance. In recent years, proteins in this family have been identified as drug targets in the design of new... (Review)
Review
Bcl-2 proteins are key determinants in the life-death balance. In recent years, proteins in this family have been identified as drug targets in the design of new anti-tumor therapies. Advances in the knowledge of the mechanism of action of anti-apoptotic and pro-apoptotic members of the Bcl-2 family have enabled the development of the so-called 'BH3 mimetics'. These compounds act by inhibiting anti-apoptotic proteins of the family, imitating the function of the BH3-only subset of pro-apoptotic members. Combinations of BH3-mimetics with anti-tumor drugs are being evaluated in both preclinical models and clinical trials. Recent advances in these approaches will be reviewed.
Topics: Animals; Antineoplastic Agents; Apoptosis; BH3 Interacting Domain Death Agonist Protein; Biomimetic Materials; Drug Delivery Systems; Humans; Proto-Oncogene Proteins c-bcl-2
PubMed: 26079328
DOI: 10.1016/j.coph.2015.05.014