Targeting cisplatin-resistant human tumor cells with metabolic inhibitors

Sullivan, Elizabeth J.; Kurtoğlu, Metin; Brenneman, Randall; Liu, Huaping; Lampidis, Théodore J.

doi:10.1007/s00280-013-2366-8

Cited by 42 publications

(39 citation statements)

References 22 publications

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“…Such inherent differences were also observed in the LDHA and lactate levels after treatment with miR34a HA-NPs between the cisplatin sensitive and cisplatin resistant A549 and A549 DDP cells. This is consistent with the previous findings which depict the role of LDHA levels for acquired platinum resistance in cancer 82, 83 .…”

Section: Discussionsupporting

confidence: 94%

MicroRNA-34a Encapsulated in Hyaluronic Acid Nanoparticles Induces Epigenetic Changes with Altered Mitochondrial Bioenergetics and Apoptosis in Non-Small-Cell Lung Cancer Cells

Trivedi

Singh

Talekar

et al. 2017

Sci Rep

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Therapies targeting epigenetic changes for cancer treatment are in Phase I/II trials; however, all of these target only nuclear DNA. Emerging evidence suggests presence of methylation marks on mitochondrial DNA (mtDNA); but their contribution in cancer is unidentified. Expression of genes encoded on mtDNA are altered in cancer cells, along with increased glycolytic flux. Such glycolytic flux and elevated reactive oxygen species is supported by increased antioxidant; glutathione. MicroRNA-34a can translocate to mitochondria, mediate downstream apoptotic effects of tumor suppressor P53, and inhibit the antioxidant response element Nrf-2, resulting in depleted glutathione levels. Based on such strong rationale, we encapsulated microRNA-34a in our well-established Hyaluronic-Acid nanoparticles and delivered to cisplatin-sensitive and cisplatin-resistant A549-lung adenocarcinoma cells. Successful delivery and uptake in cells resulted in altered ATP levels, decreased glycolytic flux, Nrf-2 and glutathione levels, ultimately resulting in caspase-3 activation and apoptosis. Most important were the concurrent underlying molecular changes in epigenetic status of D-loop on the mtDNA and transcription of mtDNA-encoded genes. Although preliminary, we provide a novel therapeutic approach in form of altered mitochondrial bioenergetics and redox status of cancer cells with underlying changes in epigenetic status of mtDNA that can subsequently results in induction of cancer cell apoptosis.

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Section: Discussionsupporting

confidence: 94%

MicroRNA-34a Encapsulated in Hyaluronic Acid Nanoparticles Induces Epigenetic Changes with Altered Mitochondrial Bioenergetics and Apoptosis in Non-Small-Cell Lung Cancer Cells

Trivedi

Singh

Talekar

et al. 2017

Sci Rep

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“…Preclinical studies have shown enhanced anti-tumor activity in pancreatic models with a variety of drugs including gemcitabine [34]. Cisplatin has demonstrated enhanced cytotoxicity in combination with 2-DG in head and neck cancer cells and in lung cancer cell lines [35,36]. Cisplatin-resistant cancer cell lines with decreased hexokinase levels have been shown to be more sensitive to the combined activity of cisplatin with 2-DG or 2-fluorodeoxyglucose [31].…”

Section: Discussionmentioning

confidence: 99%

The anti-tumor efficacy of 2-deoxyglucose and D-allose are enhanced with p38 inhibition in pancreatic and ovarian cell lines

Malm

Hanke

Gill

et al. 2015

J Exp Clin Cancer Res

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PurposeThe anti-tumor activity of glucose analogs 2-deoxy-glucose (2-DG) and D-allose was investigated alone or in combination with p38 mitogen-activated protein kinase (MAPK) inhibitor SB202190 or platinum analogs as a strategy to pharmacologically target glycolytic tumor phenotypes.MethodsHypoxia inducible factor-1 alpha (HIF-1α) protein accumulation in pancreatic cell lines treated with SB202190 alone and in combination with glucose analogs was analyzed by Western blot. HIF-1α transcriptional activity was measured in MIA PaCa-2 cells stably transfected with a hypoxia response element luciferase reporter following treatment with glucose analogs alone, and in combination with SB202190. Induction of cleaved poly(ADP-ribose) polymerase (PARP) was measured by Western blot in the MIA PaCa-2 cells. In vitro anti-proliferative activity of 2-DG and D-allose alone, or in combination with oxaliplatin (pancreatic cell lines), cisplatin (ovarian cell lines), or with SB202190 were investigated using the MTT assay.ResultsSB202190 decreased HIF-1α protein accumulation and transcriptional activity. 2-DG demonstrated greater anti-proliferative activity than D-allose. Pre-treatment with SB202190 enhanced activity of both 2-DG and D-allose in MIA PaCa-2, BxPC-3, ASPC-1, and SK-OV-3 cells. The combination of D-allose and platinum agents was additive to moderately synergistic in all but the OVCAR-3 and HEY cells. SB202190 pre-treatment further enhanced activity of D-allose and 2-DG with platinum agents in most cell lines investigated.ConclusionsSB202190 induced sensitization of tumor cells to 2-DG and D-allose may be partially mediated by inhibition of HIF-1α activity. Combining glucose analogs and p38 MAPK inhibitors with chemotherapy may be an effective approach to target glycolytic tumor phenotypes.

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“…Knockdown of HK-II with siRNA reduces its mRNA and protein levels, as well as its activity, resulting in cell cycle arrest at the G1 phase, attenuated glycolysis, and apoptosis in cancer cells [31, 76–78]. Silencing of the HK-II gene sensitizes human colon cancer cells to 5-fluorouracil [79] and sensitizes parental lung cancer cells to cisplatin [80]. In addition, the combination of HK-II interference and 131 I therapy demonstrated a stronger anticancer effect in anaplastic thyroid carcinoma cells [81].…”

Section: Agents Targeted Inhibiting the Hk-ii-mediated Warburg Effectmentioning

confidence: 99%

Warburg effect, hexokinase-II, and radioresistance of laryngeal carcinoma

Zhong

Zhou

2016

Oncotarget

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Radiotherapy is now widely used as a part of multidisciplinary treatment approaches for advanced laryngeal carcinoma and preservation of laryngeal function. However, the mechanism of the radioresistance is still unclear. Some studies have revealed that the Warburg effect promotes the radioresistance of various malignant tumors, including laryngeal carcinoma. Among the regulators involved in the Warburg effect, hexokinase-II (HK-II) is a crucial glycolytic enzyme that catalyzes the first essential step of glucose metabolism. HK-II is reportedly highly expressed in some human solid carcinomas by many studies. But for laryngeal carcinoma, there is only one. Till now, no studies have directly targeted inhibited HK-II and enhanced the radiosensitivity of laryngeal carcinoma. Accumulating evidence has shown that dysregulated signaling pathways often result in HK-II overexpression. Here, we summarize recent advances in understanding the association among the Warburg effect, HK-II, and the radioresistance of laryngeal carcinoma. We speculate on the feasibility of enhancing radiosensitivity by targeted inhibiting HK-II signaling pathways in laryngeal carcinoma, which may provide a novel anticancer therapy.

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Targeting cisplatin-resistant human tumor cells with metabolic inhibitors

Cited by 42 publications

References 22 publications

MicroRNA-34a Encapsulated in Hyaluronic Acid Nanoparticles Induces Epigenetic Changes with Altered Mitochondrial Bioenergetics and Apoptosis in Non-Small-Cell Lung Cancer Cells

MicroRNA-34a Encapsulated in Hyaluronic Acid Nanoparticles Induces Epigenetic Changes with Altered Mitochondrial Bioenergetics and Apoptosis in Non-Small-Cell Lung Cancer Cells

The anti-tumor efficacy of 2-deoxyglucose and D-allose are enhanced with p38 inhibition in pancreatic and ovarian cell lines

Warburg effect, hexokinase-II, and radioresistance of laryngeal carcinoma

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