Differential sensitivity of human colon cancer cell lines to the nucleoside analogs ARC and DRB

Bhat, Uppoor G.; Gartel, Andrei L.

doi:10.1002/ijc.23239

Cited by 12 publications

(20 citation statements)

References 17 publications

(35 reference statements)

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“…The mechanism whereby clofarabine-bortezomib treatment reduces survivin levels in HCT-116 xenografts could be either p53-dependent (41), as indicated by our Western blot analysis (Supplementary Fig. S1E), or p53-independent (42). Regardless, the greater-than-single-agent activity of this combination has some precedent; previous in vitro experiments have demonstrated that bortezomib-induced cytotoxicity and pro-apoptotic signaling are enhanced by purine nucleoside analogs (43).…”

Section: Discussionmentioning

confidence: 82%

The National Cancer Institute ALMANAC: A Comprehensive Screening Resource for the Detection of Anticancer Drug Pairs with Enhanced Therapeutic Activity

et al. 2017

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To date, over 100 small molecule oncology drugs have been approved by the US Food and Drug Administration. Due to the inherent heterogeneity of tumors, these small molecules are often administered in combination to prevent emergence of resistant cell subpopulations. Therefore, new combination strategies to overcome drug resistance in patients with advanced cancer are needed. In this study, we performed a systematic evaluation of the therapeutic activity of over 5,000 pairs of FDA-approved cancer drugs against a panel of 60 well-characterized human tumor cell lines (NCI-60) to uncover combinations with greater than additive growth-inhibitory activity. Screening results were compiled into a database, termed the NCI-ALMANAC (A Large Matrix of Anti Neoplastic Agent Combinations), publically available at https://dtp.cancer.gov/ncialmanac. Subsequent in vivo experiments in mouse xenograft models of human cancer confirmed combinations with greater than single-agent efficacy. Concomitant detection of mechanistic biomarkers for these combinations in vivo supported the initiation of two phase I clinical trials at the NCI to evaluate clofarabine with bortezomib and nilotinib with paclitaxel in patients with advanced cancer. Consequently, the hypothesis-generating NCI-ALMANAC web-based resource has demonstrated value in identifying promising combinations of approved drugs with potent anticancer activity for further mechanistic study and translation to clinical trials.

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Section: Discussionmentioning

confidence: 82%

The National Cancer Institute ALMANAC: A Comprehensive Screening Resource for the Detection of Anticancer Drug Pairs with Enhanced Therapeutic Activity

et al. 2017

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“…Similarly, the altered expression of anti-apoptotic Bcl-2 family proteins can confer the tumor cells with TRAIL resistance [12], [21], [24], [44], [45], [46], [61], [62], [63]. It has also been shown that anti-apoptotic protein survivin is highly expressed in colon carcinoma cells [64], [65]. These observations suggest that TRAIL resistance mechanisms might be tumor type and stage-dependent.…”

Section: Discussionmentioning

confidence: 96%

TNFα Cooperates with IFN-γ to Repress Bcl-xL Expression to Sensitize Metastatic Colon Carcinoma Cells to TRAIL-mediated Apoptosis

Liu

Zimmerman

et al. 2011

PLoS ONE

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BackgroundTNF-related apoptosis-inducing ligand (TRAIL) is an immune effector molecule that functions as a selective anti-tumor agent. However, tumor cells, especially metastatic tumor cells often exhibit a TRAIL-resistant phenotype, which is currently a major impediment in TRAIL therapy. The aim of this study is to investigate the synergistic effect of TNFα and IFN-γ in sensitizing metastatic colon carcinoma cells to TRAIL-mediated apoptosis.Methodology/Principal FindingsThe efficacy and underlying molecular mechanism of cooperation between TNFα and IFN-γ in sensitizing metastatic colon carcinoma cells to TRAIL-mediated apoptosis were examined. The functional significance of TNFα- and IFN-γ-producing T lymphocyte immunotherapy in combination with TRAIL therapy in suppression of colon carcinoma metastasis was determined in an experimental metastasis mouse model. We observed that TNFα or IFN-γ alone exhibits minimal sensitization effects, but effectively sensitized metastatic colon carcinoma cells to TRAIL-induced apoptosis when used in combination. TNFα and IFN-γ cooperate to repress Bcl-xL expression, whereas TNFα represses Survivin expression in the metastatic colon carcinoma cells. Silencing Bcl-xL expression significantly increased the metastatic colon carcinoma cell sensitivity to TRAIL-induced apoptosis. Conversely, overexpression of Bcl-xL significantly decreased the tumor cell sensitivity to TRAIL-induced apoptosis. Furthermore, TNFα and IFN-γ also synergistically enhanced TRAIL-induced caspase-8 activation. TNFα and IFN-γ was up-regulated in activated primary and tumor-specific T cells. TRAIL was expressed in tumor-infiltrating immune cells in vivo, and in tumor-specific cytotoxic T lymphocytes (CTL) ex vivo. Consequently, TRAIL therapy in combination with TNFα/IFN-γ-producing CTL adoptive transfer immunotherapy effectively suppressed colon carcinoma metastasis in vivo.Conclusions/SignificanceTNFα and IFN-γ cooperate to overcome TRAIL resistance at least partially through enhancing caspase 8 activation and repressing Bcl-xL expression. Combined CTL immunotherapy and TRAIL therapy hold great promise for further development for the treatment of metastatic colorectal cancer.

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“…In myeloma cells, while RGB 286638 clearly depleted Pol II CTD Ser2 phosphorylation, cytotoxicity was associated with both CDK-dependent and -independent inhibition [86]. The compound ARC [4-amino-6-hydrazino-7-β- D -ribofuranosyl-7H-pyrrolo(2,3-d)-pyrimidine-5-carboxamide; Figure 4(i)] has been shown to induce apoptosis in several types of cancer cells due to its depletion of anti-apoptotic proteins such as MCL-1 and survivin [40,41,108-110]. Using purified P-TEFb in an in vitro kinase assay on a recombinant Pol II CTD, ARC was shown to inhibit this kinase [41].…”

Section: Therapeutic Inhibitors Of Mrna Synthesismentioning

confidence: 99%

Transcription Inhibition as a Therapeutic Target for Cancer

Stellrecht

Chen

2011

Cancers

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During tumorigenesis the transformed cells lose their normal growth control mechanisms and become dependent on oncogenes' products and pathways for survival. Treatments tailored to block the expression or function of transforming genes have shown efficacy in eliminating neoplastic cells. The mRNAs of many oncogenes, as well as regulators of other key processes such as cell proliferation, angiogenesis, and apoptosis, typically have shorter half-lives. Agents that impede mRNA synthesis are expected to selectively hinder the expression of these genes and, therefore, be detrimental to neoplastic cells that are physiologically dependent on them. In addition to exploiting the tumor cells' dependency on short-lived transcripts, RNA-directed agents also take advantage of the differential sensitivity between transformed and non-transformed cells, as the cytotoxic effects of inhibiting RNA synthesis have not been seen in non-transformed cells. The abrogation of the formation of oncotranscripts provides a new concept in cancer therapeutics and numerous agents have been developed which are able to target transcription. The focus of this review is to give an overview of transcription and the different inhibitory strategies that target various aspects of the transcriptional process.

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Differential sensitivity of human colon cancer cell lines to the nucleoside analogs ARC and DRB

Cited by 12 publications

References 17 publications

The National Cancer Institute ALMANAC: A Comprehensive Screening Resource for the Detection of Anticancer Drug Pairs with Enhanced Therapeutic Activity

The National Cancer Institute ALMANAC: A Comprehensive Screening Resource for the Detection of Anticancer Drug Pairs with Enhanced Therapeutic Activity

TNFα Cooperates with IFN-γ to Repress Bcl-xL Expression to Sensitize Metastatic Colon Carcinoma Cells to TRAIL-mediated Apoptosis

Transcription Inhibition as a Therapeutic Target for Cancer

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