Synthetic Lethality of a Novel Small Molecule Against Mutant KRAS-Expressing Cancer Cells Involves AKT-Dependent ROS Production

Iskandar, Kartini; Rezlan, Majidah; Yadav, Sushma; Foo, Chuan Han Jonathan; Sethi, Gautam; Yu, Qiang; Bellot, Gaëtan; Pervaiz, Shazib

doi:10.1089/ars.2015.6362

Cited by 32 publications

(29 citation statements)

References 37 publications

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“…This is in agreement with our earlier findings indicating B-cell lymphoma-derived cell lines were resistant to etoposide and other chemotherapeutic drugs. Interestingly, we provide evidence that primary BL cells were relatively more responsive to the experimental small molecules MPO[18], MPO-Zn (MPO analogue) and C1 [16, 17] (Figure 1b). We also tested the sensitivity of primary BL cells to the death receptor ligand TRAIL.…”

Section: Resultsmentioning

confidence: 96%

“…Primary cells were then subjected ex vivo to apoptotic stimuli, including the commonly used chemotherapeutic agents etoposide (1-10μM), daunorubicin (0.2-0.8μg/ml), vincristine (1-10μM), the death receptor ligand TRAIL (50-200ng/ml), as well as experimental small molecule compounds LY30 (25-50μM) [15], C1 (25-100μg/ml) [16, 17], MPO (1-10μM) [18], and MPO-Zn (100-400nM). As an internal control, two established cell lines, Raji and Jurkat, were used in parallel.…”

Section: Resultsmentioning

confidence: 99%

“…Two of the molecules (LY30 and C1) have been previously reported by our group to target tumor cells via mechanisms involving an increase in intracellular ROS [15-17, 23]. As ROS have been linked to membrane lipid peroxidation and disruption of lipid rafts, we asked if the ability of C1 and LY30 to dislodge Apaf-1 from the lipid rafts was a function of intracellular ROS production.…”

Section: Resultsmentioning

confidence: 99%

“…Although, we do not have experimental evidence to suggest differences in the membrane composition between primary cells derived from B and T cell lymphomas, results presented with small molecule experimental compounds appear to support these observations. Two small molecule experimental agents, C1 [16, 17] and LY30 [15, 23], as well as the mitochondria electron transport inhibitor NaN 3 that trigger intracellular ROS production had a profound influence on cell-free caspase 3 activity as a result of the re-localization of Apaf-1 to the cytosol. To that end, redox-dependent alterations of lipid moieties could disrupt lipid raft structures thereby facilitating the release of sequestered Apaf-1.…”

Section: Discussionmentioning

confidence: 99%

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Aberrant localization of apoptosis protease activating factor-1 in lipid raft sub-domains of diffuse large B cell lymphomas

Hirpara

Loh

et al. 2016

Oncotarget

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Resistance to chemotherapy remains a challenge in the clinical management of diffuse B cell lymphomas despite aggressive chemotherapy such as CHOP and monoclonal CD20. Here we provide evidence that the apoptosome adaptor protein, Apaf-1, is mislocalized in primary cells derived from patients with diffuse large B cell lymphomas (DLBCL). Whereas, the total expression of Apaf-1 did not change, its sub-cellular localization was significantly different in DLBCL, compared to T cell lymphomas as well as cells derived from reactive lymphadenopathy biopsies. As expected, Apaf-1 was detected in the cytosolic fractions of non-B cell lymphomas and non-cancerous tissues; however, in B cell derived lymphomas the protein was detected in membrane raft sub-domains rather than the cytosol. Disruption of lipid raft structures resulted in the redistribution of Apaf-1 to the cytosol and restored apoptosis sensitivity of DLBCL. Furthermore, we identified novel small molecule compounds that target DLBCL by promoting Apaf-1 release form lipid rafts via mechanisms that involve an increase in intracellular reactive oxygen species production. Taken together, our results implicate Apaf-1 mislocalization as a potential diagnostic and prognostic marker for DLBCL, and provide a novel therapeutic strategy for circumventing the drug refractory nature of this sub-class of B cell lymphoma.

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Section: Resultsmentioning

confidence: 96%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Aberrant localization of apoptosis protease activating factor-1 in lipid raft sub-domains of diffuse large B cell lymphomas

Hirpara

Loh

et al. 2016

Oncotarget

Self Cite

View full text Add to dashboard Cite

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“…Furthermore, the activation of HK-II by mitochondrial Akt had an anti-apoptotic effect on the cells [308]. In contrast, a pro-apoptotic role of Akt was seen in HCT11 cells expressing a mutant k-ras oncogene; Akt rapidly translocated into the mitochondria and increased ROS production, leading to cell death [155]. …”

Section: Disparities At the Nuclear Genome Level And Their Role Inmentioning

confidence: 99%

Mitochondrial determinants of cancer health disparities

Choudhury

Singh

2017

Seminars in Cancer Biology

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Mitochondria are involved in the generation of energy, cell growth and differentiation, cellular signaling, cell cycle control, and cell death. To date, the mitochondrial basis of cancer disparities is unknown. The goal of this review is to provide an understanding and a framework of mitochondrial determinants that may contribute to cancer disparities in racially different populations. Mitochondria, which are multi-functional, have been implicated in the initiation and progression of cancers in relation to metabolic alterations in transformed cells. Due to ethnic-based diversity, the mitochondrial genome (mtDNA) could be a basis for inherited racial disparities and for acquired somatic mutations during tumorigenesis. In African Americans, several germline, population-specific haplotype variants in mtDNA as well as depletion of mtDNA have been linked to cancer predisposition and cancer disparities. Indeed, depletion of mtDNA and mutations in mtDNA or nuclear genome (nDNA)-encoded mitochondrial proteins lead to mitochondrial dysfunction and promote resistance to apoptosis, the epithelial-to-mesenchymal transition, and metastatic disease, which in turn can contribute to cancer disparity and tumor aggressiveness related to racial disparities. Ethnic differences at the level of expression or genetic variations in nDNA encoding the mitochondrial proteome, including mitochondria-localized mtDNA replication and repair proteins, miRNA, transcription factors, kinases and phosphatases, and tumor suppressors and oncogenes may underlie susceptibility to high-risk and aggressive cancers found in African Americans and other ethnicities. The mitochondrial retrograde signaling that alters the expression profile of nuclear genes in response to dysfunctional mitochondria is a mechanism for tumorigenesis. In ethnic populations, differences in mitochondrial function may alter the cross talk between mitochondria and the nucleus at epigenetic and genetic levels, which can also contribute to cancer health disparities. Targeting mitochondrial determinants and mitochondrial retrograde signaling could provide a promising strategy for the development of selective anticancer therapy for dealing with cancer disparities. Further, agents that restore mitochondrial function to optimal levels should permit sensitivity to anticancer agents for the treatment of aggressive tumors that occur in racially diverse populations and hence help in reducing racial disparities.

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In vitro assays and techniques utilized in anticancer drug discovery

Ediriweera

Tennekoon

Samarakoon

2018

J of Applied Toxicology

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Development of a cancer is a multistep process and six major hallmarks of cancer that are known to control malignant transformation have been described. Anticancer drug development is a tedious process, requiring a number of in vitro, in vivo and clinical studies. In vitro assays provide an initial platform for cancer drug discovery approaches. A wide range of in vitro assays/techniques have been developed to evaluate each hallmark feature of cancer and selection of a particular in vitro assay or technique mainly depends on the specific research question (s) to be examined. In the present review, we have described some commonly utilized in vitro assays and techniques used to examine cell viability/proliferation, apoptosis, cellular senescence, invasion and migration, oxidative stress and antioxidant effects, gene and protein expression, angiogenesis and genomic alterations in cancer drug discovery. Additionally, uses of modern techniques such as high throughput screening, high content screening and reporter gene assays in cancer drug discovery have also been described.

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Synthetic Lethality of a Novel Small Molecule Against Mutant KRAS-Expressing Cancer Cells Involves AKT-Dependent ROS Production

Abstract: These data indicate a synthetic lethal effect against cells carrying mutant KRAS, which could have therapeutic implications given the paucity of KRAS-specific chemotherapeutic strategies. Antioxid. Redox Signal. 24, 781-794.

Cited by 32 publications

References 37 publications

Aberrant localization of apoptosis protease activating factor-1 in lipid raft sub-domains of diffuse large B cell lymphomas

Aberrant localization of apoptosis protease activating factor-1 in lipid raft sub-domains of diffuse large B cell lymphomas

Mitochondrial determinants of cancer health disparities

In vitro assays and techniques utilized in anticancer drug discovery

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