Bortezomib With or Without Irinotecan in Relapsed or Refractory Colorectal Cancer: Results From a Randomized Phase II Study

Kozuch, Peter; Rocha-Lima, Caio; Dragovich, Tomislav; Hochster, Howard S.; O’Neil, Bert H.; Atiq, Omar; Pipas, J. Marc; Ryan, David P.; Lenz, Heinz Josef

doi:10.1200/jco.2007.14.0152

Cited by 39 publications

(30 citation statements)

References 46 publications

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“…As a result, proteasome inhibitors have a narrow therapeutic index. Bortezomib targets the 20S proteasome catalytic core, attenuating cell proliferation and survival, and has proven effect in metastatic colorectal cancer (Kozuch et al, 2008). Other mechanisms seen in cancer cells treated with this drug include reports of upregulation of pro-survival proteins in response to proteasome inhibition (Milano et al, 2009), and stability of p53 expression in treated cells and tissues, although pro-apoptotic effects are also demonstrated in cells which do not express p53 (Lenz;Ling et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Targeting the 19S proteasomal subunit, Rpt4, for the treatment of colon cancer

Boland

Flanagan

McCawley

et al. 2016

European Journal of Pharmacology

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Section: Discussionmentioning

confidence: 99%

Targeting the 19S proteasomal subunit, Rpt4, for the treatment of colon cancer

Boland

Flanagan

McCawley

et al. 2016

European Journal of Pharmacology

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“…10 Results of previous bortezomib clinical trials either alone or in combination (oxaliplatin, leucovorin, and 5-fluorouracil with fluorouracil/leucovorin or irinotecan) in the setting of advanced CRC are not encouraging. [35][36][37] However, using bortezomib in combination with other biological agents through an understanding of its effects on different signaling pathways may prove more fruitful. 22,38 Our current study highlights the importance of using bortezomib to target a subgroup of CRC with aberrant UBE2C activity that lead to dysregulation of tumor growth, and this subset of patients may show positive response to bortezomib treatment.…”

Section: Discussionmentioning

confidence: 99%

Bortezomib Stabilizes Mitotic Cyclins and Prevents Cell Cycle Progression via Inhibition of UBE2C in Colorectal Carcinoma

Bavi

Uddin

Ahmed

et al. 2011

The American Journal of Pathology

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Substantial evidence implicates the ubiquitin-conjugating enzyme E2C (UBE2C) gene, in several human cancers, including colorectal carcinoma (CRC). We therefore investigated the prognostic value of UBE2C alterations in CRC and UBE2C signaling in CRC cell lines. UBE2C protein expression and UBE2C gene copy number were evaluated on clinical samples by immunohistochemistry and fluorescence in situ hybridization in a TMA format. The effect of the proteasome inhibitor bortezomib and small-interfering RNA knockdown was assessed by apoptotic assays and immunoblotting. UBE2C dysregulation was associated with proliferative marker Ki-67, accumulation of cyclin A and B1, and a poor overall survival. UBE2C expression was an independent prognostic marker in early-stage (I and II) CRC. UBE2C depletion resulted in suppression of cellular growth and accumulation of cyclin A and B1. In vitro, bortezomib treatment of CRC cells caused inhibition of cell viability via down-regulation of UBE2C. UBE2C knockdown by bortezomib or transfection with specific small-interfering RNA against UBE2C also caused cells to be arrested at the G2/M level, leading to accumulation of cyclin A and cyclin B1. In vivo, a significant reduction in tumor volume and weight was noted in mice treated with a combination of subtoxic doses of oxaliplatin and bortezomib compared with treatment with oxaliplatin or bortezomib alone. Altogether, our results suggest that UBE2C and the ubiq- Although colorectal cancer (CRC) is a major cause of mortality and morbidity worldwide, various therapeutic modalities followed in clinical practice are not life saving. More recently, advances in understanding of tumor biology have led to the development of targeted therapies, 1 allowing progress in the treatment of CRC. 2 The ubiquitin proteasome system is important for the orchestration of several important cell cycle events, such as proteolysis of cyclin-dependent kinase and their inhibitors. 3,4 Proper cell cycle progression is orchestrated by the controlled oscillation of a series of cell cycle events. Deregulation of appropriate cell cycle control often results in chromosomal instability, which is a potential trigger for the initiation of cancer. 5 In this system, substrate molecules are regulated for degradation by ubiquitinactivating enzyme (E1), ubiquitin-conjugating enzyme (E2), and E3 ligase. The ubiquitin-conjugating enzyme E2C (UBE2C), also known as UBCH10, along with the E3 ligase of the anaphase-promoting complex catalyze the ubiquitination of mitotic cyclins A and B1, as well as securin. 3,6 UBE2C is essential for cell cycle progression, and mutation of its active site cysteine confers a dominant-negative phenotype. 3,6 Overexpression of UBE2C at the mRNA level has been reported in a number of cancer cell lines and primary tumors, whereas only low levels were found in normal tissues. 7 The oncogenic role of UBE2C is also reported in thyroid, 8 ovarian, 9 esopha-

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“…Plasma cells are terminally differentiated B-cells, and bortezomib is also active in other B-cell malignancies, [3][4][5][6][7][8] but has limited efficacy in solid tumors. [9][10][11][12] One possible explanation for this difference in efficacy is the unique burden of misfolded proteins faced by malignant plasma cells, which generate large amounts of a single amino acid sequence as they produce the monoclonal immunoglobulin characteristic of myeloma. Preclinical evidence suggests that the efficacy of proteasome inhibitor therapy depends on the ability of malignant plasma cells to clear misfolded proteins through proteasomal degradation.…”

Section: Introductionmentioning

confidence: 99%