The Role of C/EBP-β LIP in Multidrug Resistance

Riganti, Chiara; Kopecka, Joanna; Panada, Elisa; Barak, Sara; Rubinstein, Menachem

doi:10.1093/jnci/djv046

Cited by 44 publications

(50 citation statements)

References 46 publications

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“…By contrast, in the resistant counterpart HT29/DX, which have higher levels of the transporter, 3 significantly increased the reduction of cell viability induced by doxorubicin when used at 1 or 10 mM (Figure 4). The same results were obtained in A549 and in A549/DX cells, characterised by high levels of P-gp 53 . A similar trend was observed also for 8 ( Figure 5).…”

Section: Co-administration Assaysupporting

confidence: 84%

“…In HT29 cells, which express low levels of P-gp 53 , neither 3 ( Figure 4) nor 8 ( Figure 5) increases the cytotoxicity, measured as reduced viability, of doxorubicin. By contrast, in the resistant counterpart HT29/DX, which have higher levels of the transporter, 3 significantly increased the reduction of cell viability induced by doxorubicin when used at 1 or 10 mM (Figure 4).…”

Section: Co-administration Assaymentioning

confidence: 96%

“…The efficacy of the compounds was next tested in cancer cell lines with various levels of P-gp, as the human adenocarcinoma colon cells (HT29) and non-small cell lung cancer cells (A549) displaying low amount of P-gp, and their resistant counterparts HT29/DX and A549/DX, with a high amount of P-gp 53 . In preliminary assays, we verified that 3 and 8 were not cytotoxic at all the tested concentration (data not shown).…”

Section: Co-administration Assaymentioning

confidence: 99%

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6,7-Dimethoxy-2-phenethyl-1,2,3,4-tetrahydroisoquinoline amides and corresponding ester isosteres as multidrug resistance reversers

Braconi

Bartolucci

Contino

et al. 2020

Journal of Enzyme Inhibition and Medicinal Chemistry

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Aiming to deepen the structure-activity relationships of the two P-glycoprotein (P-gp) modulators elacridar and tariquidar, a new series of amide and ester derivatives carrying a 6,7-dimethoxy-2-phenethyl-1,2,3,4-tetrahydroisoquinoline scaffold linked to different methoxy-substituted aryl moieties were synthesised. The obtained compounds were evaluated for their P-gp interaction profile and selectivity towards the two other ABC transporters, multidrug-resistance-associated protein-1 and breast cancer resistance protein, showing to be very active and selective versus P-gp. Two amide derivatives, displaying the best P-gp activity, were tested in co-administration with the antineoplastic drug doxorubicin in different cancer cell lines, showing a significant sensitising activity towards doxorubicin. The investigation on the chemical stability of the derivatives towards spontaneous or enzymatic hydrolysis, showed that amides are stable in both models while some ester compounds were hydrolysed in human plasma. This study allowed us to identify two chemosensitizers that behave as non-transported substrates and are characterised by different selectivity profiles.

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Section: Co-administration Assaysupporting

confidence: 84%

Section: Co-administration Assaymentioning

confidence: 96%

Section: Co-administration Assaymentioning

confidence: 99%

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6,7-Dimethoxy-2-phenethyl-1,2,3,4-tetrahydroisoquinoline amides and corresponding ester isosteres as multidrug resistance reversers

Braconi

Bartolucci

Contino

et al. 2020

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…One reason for this ICD resistance could be the active efflux of doxorubicin by Pgp that limits the drug's intracellular retention. The low amount of the drug inside the cells became insufficient to elicit ER stress [31], a key event in doxorubicin-induced ICD [2,6,7]. We thus evaluated if pharmacological inhibitors of Pgp may restore doxorubicin-induced ICD in Pgp-expressing cells.…”

Section: Discussionmentioning

confidence: 99%

Insights into P-Glycoprotein Inhibitors: New Inducers of Immunogenic Cell Death

Kopecka

Godel

Dei

et al. 2020

Cells

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Doxorubicin is a strong inducer of immunogenic cell death (ICD), but it is ineffective in P-glycoprotein (Pgp)-expressing cells. Indeed, Pgp effluxes doxorubicin and impairs the immunesensitizing functions of calreticulin (CRT), an “eat-me” signal mediating ICD. It is unknown if classical Pgp inhibitors, designed to reverse chemoresistance, may restore ICD. We addressed this question by using Pgp-expressing cancer cells, treated with Tariquidar, a clinically approved Pgp inhibitor, and R-3 compound, a N,N-bis(alkanol)amine aryl ester derivative with the same potency of Tariquidar as Pgp inhibitor. In Pgp-expressing/doxorubicin-resistant cells, Tariquidar and R-3 increased doxorubicin accumulation and toxicity, reduced Pgp activity, and increased CRT translocation and ATP and HMGB1 release. Unexpectedly, only R-3 promoted phagocytosis by dendritic cells and activation of antitumor CD8+T-lymphocytes. Although Tariquidar did not alter the amount of Pgp present on cell surface, R-3 promoted Pgp internalization and ubiquitination, disrupting its interaction with CRT. Pgp knock-out restores doxorubicin-induced ICD in MDA-MB-231/DX cells that recapitulated the phenotype of R-3-treated cells. Our work demonstrates that plasma membrane-associated Pgp prevents a complete ICD notwithstanding the release of ATP and HMGB1, and the exposure of CRT. Pharmacological compounds reducing Pgp activity and amount may act as promising chemo- and immunesensitizing agents.

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“…Cell viability was evaluated by measuring the percentage of cells stained with neutral red dye, as reported previously [38]. The viability of untreated cells was considered 100%; the results were expressed as percentage of viable cells in each experimental condition versus untreated cells.…”

Section: Methodsmentioning

confidence: 99%

P-glycoprotein-mediated chemoresistance is reversed by carbonic anhydrase XII inhibitors

et al. 2016

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Carbonic anhydrase XII (CAXII) is a membrane enzyme that maintains pH homeostasis and sustains optimum P-glycoprotein (Pgp) efflux activity in cancer cells. Here, we investigated a panel of eight CAXII inhibitors (compounds 1–8), for their potential to reverse Pgp mediated tumor cell chemoresistance. Inhibitors (5 nM) were screened in human and murine cancer cells (colon, lung, breast, bone) with different expression levels of CAXII and Pgp. We identified three CAXII inhibitors (compounds 1, 2 and 4) that significantly (≥ 2 fold) increased the intracellular retention of the Pgp-substrate and chemotherapeutic doxorubicin, and restored its cytotoxic activity. The inhibitors lowered intracellular pH to indirectly impair Pgp activity. Ca12-knockout assays confirmed that the chemosensitizing property of the compounds was dependent on active CAXII. Furthermore, in a preclinical model of drug-resistant breast tumors compound 1 (1900 ng/kg) restored the efficacy of doxorubicin to the same extent as the direct Pgp inhibitor tariquidar. The expression of carbonic anhydrase IX had no effect on the intracellular doxorubicin accumulation. Our work provides strong evidence that CAXII inhibitors are effective chemosensitizer agents in CAXII-positive and Pgp-positive cancer cells. The use of CAXII inhibitors may represent a turning point in combinatorial chemotherapeutic schemes to treat multidrug-resistant tumors.

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The Role of C/EBP-β LIP in Multidrug Resistance

Abstract: Spontaneous and drug-selected MDR cells lack LIP, which is eliminated by ubiquitin-mediated degradation. Loss of LIP drives MDR not only by increasing Pgp expression but also by a two-fold attenuation of ER stress-triggered cell death.

Cited by 44 publications

References 46 publications

6,7-Dimethoxy-2-phenethyl-1,2,3,4-tetrahydroisoquinoline amides and corresponding ester isosteres as multidrug resistance reversers

6,7-Dimethoxy-2-phenethyl-1,2,3,4-tetrahydroisoquinoline amides and corresponding ester isosteres as multidrug resistance reversers

Insights into P-Glycoprotein Inhibitors: New Inducers of Immunogenic Cell Death

P-glycoprotein-mediated chemoresistance is reversed by carbonic anhydrase XII inhibitors

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