Reversal of different drug-resistant phenotypes by an autocatalytic multitarget multiribozyme directed against the transcripts of the ABC transporters MDR1/P-gp, MRP2, and BCRP

Kowalski, Petra; Surowiak, Paweł; Lage, Hermann

doi:10.1016/j.ymthe.2004.11.016

Cited by 44 publications

(38 citation statements)

References 33 publications

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“…The MDR-1 gene confers resistance to several drugs, including paclitaxel, doxorubicin, and vincristine. Inhibitors of MDR-1 have been developed, including small molecules, ribozymes (4,5), antisense oligonucleotides (6,7), small interfering RNA (siRNA; refs. 8,9), and de novo designed artificial transcription factors (ATF; ref.…”

Section: Introductionmentioning

confidence: 99%

Modulation of drug resistance by artificial transcription factors

Blancafort

Tschan

Bergquist

et al. 2008

Molecular Cancer Therapeutics

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The efficiency of chemotherapeutic treatments in cancer patients is often impaired by the acquisition of drug resistance. Cancer cells develop drug resistance through dysregulation of one or more genes or cellular pathways. To isolate efficient regulators of drug resistance in tumor cells, we have adopted a genome-wide scanning approach based on the screening of large libraries of artificial transcription factors (ATFs) made of three and six randomly assembled zinc finger domains. Zinc finger libraries were linked to a VP64 activation domain and delivered into a paclitaxelsensitive tumor cell line. Following drug treatment, several ATFs were isolated that promoted drug resistance. One of these ATFs, 3ZF-1-VP, promoted paclitaxel resistance in cell lines having mutated or inactivated p53, such as MDA-MB-435 and Kaposi's sarcoma cell lines. 3ZF-1-VP also induced strong resistance to etoposide, vincristine, and cisplatinum. Linkage of a repression domain to the selected ATF resulted in enhanced sensitivity to multiple drugs, particularly vincristine, cisplatinum, and 5-fluorouracil. Small interfering RNA -mediated inhibition of p53 revealed that 3ZF-1-VP activated both p53-dependent and p53-independent mechanisms to promote survival, whereas other ATF required intact p53. Real-time expression analysis and DNA microarrays showed that several ATFs up-regulated targets of p53, such as the cyclin-dependent kinase inhibitor p21 WAF1/CIP1 , and genes participating in the p14 ARF

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Section: Introductionmentioning

confidence: 99%

Modulation of drug resistance by artificial transcription factors

Blancafort

Tschan

Bergquist

et al. 2008

Molecular Cancer Therapeutics

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“…19 The expression of ABCC2 was specifically reduced by antisense DNA expressed from a CMV expression A 'multitarget multiribozyme' constructed that consisted of three hammerhead motifs directed against transcripts of ABCB1, BCRP and ABCC2 specifically reduced the corresponding transporter ABCB1, BCRP and ABCC2 in all cellular systems. 21 Interestingly, it was shown that bile acid-modified oligodeoxynucleotides are secreted via ABCC2 into bile. Oligodeoxynucleotide secretion was radically diminished in a mutant Wistar rats lacking a functional ABCC2.…”

Section: Discussionmentioning

confidence: 99%

Reversal of drug resistance of hepatocellular carcinoma cells by adenoviral delivery of anti-ABCC2 antisense constructs

et al. 2007

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Human cancers are characterized by a high degree of drug resistance. The multidrug resistance transporters MDR1-P-glycoprotein (ABCB1) and ABCC2 (MRP2) are expressed in a variety of human cancers, including hepatocellular carcinoma (HCC). The ABCC2 gene encodes a membrane protein involved in the ATP-dependent transport of conjugates of lipophilic substances. In this study we analyzed the effect of an ABCC2 antisense construct on the chemosensitization of HepG2 cells. Adenoviral vectors were constructed to allow an efficient expression of anti-ABCC2 antisense constructs. The effective target sequence comprised nucleotides 2543-2942 of the human ABCC2 cDNA. Adenoviral delivery of the ABCC2 antisense construct resulted in a reduced IC 50 for doxorubicin (12-fold), vincristine (50-fold), cisplatin (25-fold) and etoposide (VP-16) (25-fold). The adenoviral delivery of the ABCC2 antisense construct was so efficient that chemosensitization of HepG2 cells could even be demonstrated in mass cell cultures without a selection of transduced cells for single ABCC2 antisense-expressing HCC cell clones. After transfection of the ABCC2 antisense-expressing construct, HepG2 cells had significantly reduced ABCC2 mRNA and ABCC2 protein levels. Transduction of the ABCC2 antisense-expressing construct into HepG2 cells resulted in the accumulation of the high-affinity ABCC2 substrate Fluo-3. HepG2 tumors stably transfected with an anti-ABCC2 antisense construct regressed significantly in nude mice upon vincristine treatment. In addition, significant tumor regression was also observed when adenovirus-expressing anti-ABCC2 antisense construct was directly injected into HepG2 tumors in nude mice. Our study demonstrates the specific reversal of ABCC2-related drug resistance in adenovirus-transduced HepG2 cells and in HepG2 tumors in nude mice expressing this ABCC2 antisense construct.

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“…Measurement of cellular anthracycline accumulation was performed by flow cytometry as described previously. 8,13,14 In brief, 1.5 x 10 6 cells were seeded in 10 cm dishes and infected with E. coli at MOIs of 1:500 on the following day. The cells were exposed to 10 μM (5.8 μg/ml) of daunorubicin for 3 h, 72 h postinfection.…”

Section: Methodsmentioning

confidence: 99%