Combined Effect of Proteasome and Calpain Inhibition on Cisplatin-Resistant Human Melanoma Cells

Młynarczuk-Biały, Izabela; Roeckmann, Heike; Kuckelkorn, Ulrike; Schmidt, Boris; Umbreen, Sumaira; Gołąb, Jakub; Ludwig, Antje; Montag, Christina; Wiebusch, Lüder; Hagemeier, Christian; Schadendorf, Dirk; Kloetzel, Peter‐M.; Seifert, Ulrike

doi:10.1158/0008-5472.can-05-2614

Cited by 47 publications

(41 citation statements)

References 33 publications

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“…Pharmacological inhibitors of the catalytic activity of calpains overcome resistance to TRAIL in colon cancer (Zhu et al, 2004), cisplatin in melanoma (Mlynarczuk-Bialy et al, 2006) or androgen independence of prostate cancer (Libertini et al, 2007). In this study, we provide evidence that calpain regulates trastuzumab sensitivity and survival of HER2-positive breast cancer cells, deregulation of calpain promotes deregulation of the activation of HER2 and PTEN/ AKT1, and inhibitors of calpain activity rescue trastuzumab resistance.…”

Section: Introductionmentioning

confidence: 69%

“…In other examples of cancer therapy including TRAIL, cisplatin or androgens, calpain-induced proteolytic events alter regulation of caspases, NF-kb or androgen receptor, and thereby contribute to resistance (Zhu et al, 2004;Mlynarczuk-Bialy et al, 2006;Libertini et al, 2007). Here, analysis of trastuzumab sensitivity in the model of acquired trastuzumab resistance indicates that the deregulation of the activation of calpain occurs during acquisition of resistance that correlates with the deregulation of cleavage and activity of HER2.…”

Section: Regulation Of Her2mentioning

confidence: 93%

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Calpain regulates sensitivity to trastuzumab and survival in HER2-positive breast cancer

et al. 2009

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Resistance to anti-HER2 (human epithelial growth factor receptor 2) trastuzumab therapy occurs commonly in HER2-positive breast cancer and involves overactivation of HER2 and/or AKT1. Using the model of trastuzumabsensitive or trastuzumab-resistant HER2-positive cells with wild-type PTEN, negative regulator of AKT1, we explore the involvement of cysteine protease calpain in mechanisms of trastuzumab resistance. Overexpression of calpain1 or activation of endogenous calpain during adhesion or trastuzumab treatment of trastuzumabsensitive cells induces cleavage of cytoplasmic domains of HER2/phospho-HER2; cleavage occurs in HER2-positive tumors. Expression of the catalytically inactive mutant of calpain1 reduces the cleavage to enhance the activity of HER2, inactivates PTEN to enhance the activation of AKT1, induces desensitization to trastuzumab and promotes survival of trastuzumab-sensitive cells. In the model of trastuzumab resistance, constitutive overactivation of HER2 and AKT1 correlates with reduced activation of calpain. Moreover, inhibitors of the catalytic site of calpain reduce the increase in constitutive activity of AKT1 and survival of trastuzumab-resistant cells selectively. Together, by regulating the activation of HER2 and PTEN/AKT1, calpain regulates trastuzumab sensitivity and survival, and the deregulation of the activation of calpain promotes trastuzumab resistance. Trastuzumab-resistant cells activate AKT1 in a mechanism dependent on the residual calpain activity, inhibition of which restores trastuzumab sensitivity and rescues resistance. These data identify calpain as a new therapeutic target in HER2-positive breast cancer.

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Section: Introductionmentioning

confidence: 69%

Section: Regulation Of Her2mentioning

confidence: 93%

Calpain regulates sensitivity to trastuzumab and survival in HER2-positive breast cancer

et al. 2009

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“…It is also notable that recent data point to an increase in calpain activity in proteasome-inhibited cells, 56 as well as in a cisplatin-resistant melanoma cell line. 57 These findings suggest that IPSI-001, or other calpain inhibitors, may prove to be useful in combination therapies where the dual calpain/20S i inhibitory activity may be able to target more pathways of resistance activated by malignant cells.…”

Section: Discussionmentioning

confidence: 94%

Targeted inhibition of the immunoproteasome is a potent strategy against models of multiple myeloma that overcomes resistance to conventional drugs and nonspecific proteasome inhibitors

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et al. 2009

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Proteasome inhibition is a validated strategy for therapy of multiple myeloma, but this disease remains challenging as relapses are common, and often associated with increasing chemoresistance. Moreover, nonspecific proteasome inhibitors such as bortezomib can induce peripheral neuropathy and other toxicities that may compromise the ability to deliver therapy at full doses, thereby decreasing efficacy. One novel approach may be to target the immunoproteasome, a proteasomal variant found predominantly in cells of hematopoietic origin that differs from the constitutive proteasome found in most other cell types. Using purified preparations of constitutive and immunoproteasomes, we screened a rationally designed series of peptidyl-aldehydes and identified several with relative specificity for the immunoproteasome. The most potent immunoproteasome-specific inhibitor, IPSI-001, preferentially targeted the ␤1 i subunit of the immunoproteasome in vitro and in cellulo in a dose-dependent manner. This agent induced accumulation of ubiquitin-protein conjugates, proapoptotic proteins, and activated caspasemediated apoptosis. IPSI-001 potently inhibited proliferation in myeloma patient samples and other hematologic malignancies. Importantly, IPSI-001 was able to overcome conventional and novel drug resistance, including resistance to bortezomib. These findings provide a rationale for the translation of IPSIs to the clinic, where they may provide antimyeloma activity with greater specificity and less toxicity than current inhibitors.

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“…One of the practical approaches that has been used to circumvent resistance of cancer cells to chemotherapeutics is combination therapy, or polychemotherapy, which uses multiple drugs to target cancer cells. Combination therapy with multiple drugs can achieve therapeutic effects greater than those provided singly by each drug [22,23].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of nuclear factor kappa B transcription activity drives a synergistic effect of pyrrolidine dithiocarbamate and cisplatin for treatment of renal cell carcinoma

et al. 2009

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One of the impeding factors in the effective treatment of metastatic renal cell carcinoma (RCC) is their intrinsic and acquired resistance to chemotherapeutics. Many studies have shown that drug resistance, at least in part, is mediated by the upregulation of anti-apoptotic (Bcl-2) and multidrug resistance molecules (MDR-1 and MRP-1) by the transcription factor nuclear factor kappa B (NF-kappaB). Combining NF-kappaB inhibitors with conventional chemotherapeutics could overcome resistance of cancer cells. In this study, we examined the synergistic effect of pyrrolidine dithiocarbamate (PDTC), a NF-kappaB inhibitor, and cisplatin, on two human metastatic RCC cell lines ACHN and SN12K1. Individual non-toxic concentrations of PDTC and cisplatin, when combined, synergistically induced a significant increase in apoptosis of the two RCC cell lines. In ACHN cells, the groups with nuclear translocation of NF-kappaB showed resistance to apoptosis, but in SN12K1 cells, the groups with NF-kappaB translocation were susceptible to apoptosis. The combination treatment significantly decreased the transcription activity of all NF-kappaB subunits in both cell lines. Anti-apoptotic proteins Bcl-2 and Bcl-(XL) were significantly decreased in the combination therapy group of both cell lines, but MDR-1 was decreased only in the ACHN cells. No changes in MRP-1 were observed in any of the treatment groups. The results demonstrate the potential of PDTC to be an adjunct therapeutic agent. The major mechanism of the synergistic effect appears to be mediated by the inhibition of transcription activity of NF-kappaB rather than its expression, and the resultant decrease in the anti-apoptotic proteins Bcl-2 and Bcl-(XL).

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Combined Effect of Proteasome and Calpain Inhibition on Cisplatin-Resistant Human Melanoma Cells

Abstract: Resistance of tumor cells to cisplatin is a common feature frequently encountered during chemotherapy against melanoma caused by various known and unknown mechanisms.

Cited by 47 publications

References 33 publications

Calpain regulates sensitivity to trastuzumab and survival in HER2-positive breast cancer

Calpain regulates sensitivity to trastuzumab and survival in HER2-positive breast cancer

Targeted inhibition of the immunoproteasome is a potent strategy against models of multiple myeloma that overcomes resistance to conventional drugs and nonspecific proteasome inhibitors

Inhibition of nuclear factor kappa B transcription activity drives a synergistic effect of pyrrolidine dithiocarbamate and cisplatin for treatment of renal cell carcinoma

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