Clinical multidrug resistance in cancer: A multifactorial problem

Lehnert, Manfred

doi:10.1016/0959-8049(96)00069-x

Cited by 158 publications

(87 citation statements)

References 74 publications

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“…1 Increased expression and drug efflux by ATP-binding cassette (ABC) drug transporters, particularly Abcb1 (Mdr1, P-glycoprotein), have been extensively shown to mediate MDR in vitro. 2,3 Although the contribution of Abcb1 to MDR is well known, the mechanism by which it becomes upregulated in tumor cells remains unclear.…”

Section: Introductionmentioning

confidence: 99%

The temporal relationship between ABCB1 promoter hypomethylation, ABCB1 expression and acquisition of drug resistance

et al. 2010

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Induced expression of the Abcb1 drug transporter often occurs in tumors in response to chemotherapy. The role that epigenetic modifications within the ABCB1 promoter play in Abcb1 expression remains unclear. We selected MCF-7 cells for survival in increasing doses of chemotherapy drugs, and assessed the methylation status of 66 CpG sites within the ABCB1 promoter preceding, accompanying and following the onset of drug resistance. Increased ABCB1 transcript expression coincident with acquisition of resistance to epirubicin or paclitaxel was temporally associated with hypomethylation of the ABCB1 downstream promoter in the absence of gene amplifications or changes in mRNA stability. Treatment of control MCF-7 cells with demethylating and/or acetylating agents increased ABCB1 transcript expression. In addition to broad promoter hypomethylation, dramatic reductions in the methylation of specific CpG sites within the promoter were observed, suggesting that these sites may play a predominant role in transcriptional activation through promoter hypomethylation. Furthermore, our data suggest that allele-specific reductions in ABCB1 promoter methylation regulate promoter usage within paclitaxel-resistant cells. This study provides strong evidence that changes in ABCB1 promoter methylation, ABCB1 promoter usage and ABCB1 transcript expression can be temporally and causally correlated with the acquisition of drug resistance in breast tumor cells.

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Section: Introductionmentioning

confidence: 99%

The temporal relationship between ABCB1 promoter hypomethylation, ABCB1 expression and acquisition of drug resistance

et al. 2010

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“…P-glycoprotein (P-gp), an energy-dependent drug efflux pump shown to confer multidrug resistance (MDR) Pastan, 1988, 1993;Lehnert, 1996;Germann, 1996) 2. alterations in β-tubulin isotypes (Haber et al, 1995;Ranganathan et al, 1988Kavallaris et al, 1997 3. mutations in tubulins (Cabral et al, 1981;Schibler and Cabral, 1986;Giannakakou et al, 1997) 4. up-regulation of caveolin-1 (Yang et al, 1998).…”

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confidence: 99%

Modulation of paclitaxel resistance by annexin IV in human cancer cell lines

Han¹,

Tahir²,

Cherian³

et al. 2000

Br J Cancer

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Efficacy of paclitaxel in cancer patients has been hampered by the ability of cells to develop paclitaxel resistance (Rowinsky et al, 1992;Rowinsky and Donehower, 1995). Therefore if we understand the mechanism of paclitaxel resistance we will be more successful in the treatment of human cancer. It has been shown that several factors contribute to paclitaxel resistance in vitro:1. P-glycoprotein (P-gp), an energy-dependent drug efflux pump shown to confer multidrug resistance (MDR) Pastan, 1988, 1993;Lehnert, 1996;Germann, 1996) 2. alterations in β-tubulin isotypes (Haber et al, 1995;Ranganathan et al, 1988Kavallaris et al, 1997 3. mutations in tubulins (Cabral et al, 1981;Schibler and Cabral, 1986;Giannakakou et al, 1997) 4. up-regulation of caveolin-1 (Yang et al, 1998.Paclitaxel also activates molecules that are involved in signal transduction pathways such as c-jun N-terminal kinase (Blagosklonny et al, 1995;Wolfson et al, 1997;Wang et al, 1998).Annexins are a family of calcium-dependent phospholipid binding proteins. There are at least 13 annexin family members with a similar structure, characterized by the presence of four or eight repeats of a 70 amino acid motif and a variable N-terminal end (Smith and Moss, 1994;Dubois et al, 1996;Benz-and Hofmann, 1997). Although the roles of the annexins are not well understood, they have been involved in various biological processes including inhibition of phospholipase A2, anticoagulation, endocytosis, exocytosis, inhibition of calcium channels and protein kinase C activity (Smith and Moss, 1994). It was also previously shown that annexin II was elevated in doxorubicin-resistant small-cell lung cancer cell line (Cole et al, 1992). During the course of our antimitotic research, we found that annexin IV was overexpressed in A204197-resistant human colon cancer HCT-15 cells as determined by two-dimensional protein mapping as well as mass spectroscopic analysis. Therefore, we tested whether annexin IV or annexin II was also overexpressed in a paclitaxel-resistant cell line, H460/T800. To our surprise annexin IV, but not annexin II, was overexpressed in the paclitaxel-resistant H460 lung cancer cell line. To further confirm the role of annexin IV in drug resistance, annexin IV cDNA was transfected into 293T cells. Annexin IV transfectants were more resistant to paclitaxel as compared to the vector controls. Thus our study indicates that annexin IV plays a role in regulating paclitaxel resistance. MATERIALS AND METHODS Cell cultureLung cancer cell line NCI-H460 (hereafter referred to as H460) and colon cancer cell line HCT15 were obtained from the American Tissue Culture Collection (ATCC) H460 and HCT15 cells were grown and maintained in RPMI medium plus 10% fetal bovine serum (FBS) or 20% FBS respectively. Paclitaxel-resistant cell lines were derived from the H460 parental cell line. H460 cells were initially selected with IC 50 concentration of paclitaxel and thereafter paclitaxel concentration was doubled every 2-3 weeks until 800 nM paclitaxel resistance was obtain...

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“…28,33,35,36 These data suggest either a technical shortcoming or that other mechanisms of drug resistance may be present in these patients such as alterations in activity and/or quantity of DNA topoisomerase II, glutathione, glutathione S-transferases, MRP and LRP, an altered intracellular drug distribution or inhibition of apoptosis. 37 Inconsistent data about the contribution of P-gp to drug resistance and treatment outcome have also been reported in childhood acute leukemia. 23,[38][39][40][41][42] We recently showed that expression of P-gp and MRP did not correlate with the intracellular DNR concentration and in vitro resistance to DNR in a large series of childhood ALL samples.…”

Section: Discussionmentioning

confidence: 99%

The modulating effect of PSC 833, cyclosporin A, verapamil and genistein on in vitro cytotoxicity and intracellular content of daunorubicin in childhood acute lymphoblastic leukemia

et al. 1998

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Resistance to anthracyclines is related to a poor prognosis in childhood acute lymphoblastic leukemia (ALL). Resistance to this class of drugs may (partly) be reversed by modulating agents, as has been demonstrated in a variety of cell lines. However, it is unknown which modulators may be of clinical benefit in childhood ALL. Therefore, we studied the modulating effect of PSC 833, cyclosporin A (CsA), verapamil (Vp) and genistein on daunorubicin (DNR) cytotoxicity, accumulation and retention in childhood ALL cells. DNR cytotoxicity was determined using the MTT assay; DNR accumulation, DNR retention and the expression of P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP) and major vault protein/lung resistance protein (LRP) were determined by flow cytometry. In the majority of samples PSC 833 (19/26), CsA (22/26) and Vp (15/18) sensitized the cells to DNR whereas genistein made 25 out of 26 samples more resistant to DNR. The sensitizing effect on the cytotoxicity of DNR was median 1.2-fold using 2 M PSC 833 (P = 0.025), 1.5-fold using 4 M CsA (P = 0.003) and 1.6-fold using 6 M Vp (P = 0.012) whereas the adverse effect of 25 M genistein was median 1.8-fold (P Ͻ 0.0001). No relationship was found between the sensitizing effect of PSC 833, CsA or Vp and the degree of DNR resistance. In contrast, the adverse effect of genistein was largest in DNR sensitive samples (P = 0.003). The effect of each modulator on the cytotoxicity of DNR did not differ between initial and relapse ALL samples although the latter were median 1.4-fold more resistant to DNR (P = 0.005). Modulation of DNR cytotoxicity was not correlated with changes in the accumulated and retained intracellular DNR content or with the expression of Pgp, MRP and LRP. Besides genistein, PSC 833, CsA and Vp incidentally made ALL cells more resistant to DNR. CsA stimulated the leukemic cell survival in seven out of 26 samples, a phenomenon that was not related to the degree of DNR resistance. In conclusion, PSC 833, CsA and Vp but not genistein may be used to sensitize cells to DNR in childhood ALL. The data also indicate that not all patients may have a therapeutic benefit from these modulators. Therefore, an in vitro culture assay may be necessary to screen for patients who may benefit by a modulator in their therapy.

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Clinical multidrug resistance in cancer: A multifactorial problem

Cited by 158 publications

References 74 publications

The temporal relationship between ABCB1 promoter hypomethylation, ABCB1 expression and acquisition of drug resistance

The temporal relationship between ABCB1 promoter hypomethylation, ABCB1 expression and acquisition of drug resistance

Modulation of paclitaxel resistance by annexin IV in human cancer cell lines

The modulating effect of PSC 833, cyclosporin A, verapamil and genistein on in vitro cytotoxicity and intracellular content of daunorubicin in childhood acute lymphoblastic leukemia

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