A novel and effective inhibitor combination involving bortezomib and OTSSP167 for breast cancer cells in light of label-free proteomic analysis

Okur, Emrah; Yerlikaya, Azmi

doi:10.1007/s10565-018-9435-z

Cited by 9 publications

(11 citation statements)

References 35 publications

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“…Currently, a small number of UPS-targeting drugs (e.g., bortezomib) are available. These drugs, which are selective proteasome inhibitors, are very effective in treating refractory melanoma and mantle cell lymphoma [26]. These findings together with our results indicate that UBB might both serve as a new therapeutic target and assist in the diagnosis of and prognosis predictions in ovarian carcinoma.…”

Section: Discussionsupporting

confidence: 58%

Integrated multi-omics analysis of genomics, epigenomics, and transcriptomics in ovarian carcinoma

Zheng

Gou

et al. 2019

Aging

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In this study, we identified prognostic biomarkers in ovarian carcinoma by integrating multi-omics DNA copy number variation (CNV) and methylation variation (MET) data. CNV, MET, and messenger RNA (mRNA) expression were examined in 351 ovarian carcinoma patients. Genes for which expression was correlated with DNA copy-number or DNA methylation were identified; three ovarian carcinoma gene subtypes were defined based on these correlations. Overall survival and B cell scores were lower, while the macrophage cell score was higher, in the DNA imprinting centre 1 (iC1) subtype than in the iC2 and iC3 subtypes. Comparison of CNV, MET, and mRNA expression among the subtypes identified two genes, ubiquitin B (UBB) and interleukin 18 binding protein (IL18BP), that were associated with prognosis. Mutation spectrum results based on subtype indicated that UBB and IL18BP expression may be influenced by mutation loci. Mutation levels were higher in iC1 samples than in iC2 or iC3 samples, indicating that the iC1 subtype is associated with disease progression. This integrated multi-omics analysis of genomics, epigenomics, and transcriptomics provides new insight into the molecular mechanisms of ovarian carcinoma and may help identify biomolecular markers for early disease diagnosis.

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Section: Discussionsupporting

confidence: 58%

Integrated multi-omics analysis of genomics, epigenomics, and transcriptomics in ovarian carcinoma

Zheng

Gou

et al. 2019

Aging

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“…The data were analyzed and graphed with GraphPad Prism 5 program. The IC 50 values of bortezomib were then obtained by using nonlinear regression to fit the data to the log(inhibitor) versus response-variable slope (Okur and Yerlikaya 2019).…”

Section: Cell Maintenance and Development Of Resistant Cellsmentioning

confidence: 99%

“…For instance, Chen and Madura showed that the proteasomal subunits, as well as the activity of the proteasome, were increased by 2-32 fold in more than 90% of primary breast cancer cells as compared to the benign solid tumors (Chen and Madura 2005). Furthermore, numerous studies showed that proteasome inhibitor bortezomib alone has significant growth suppressing and apoptotic activity in many cancer cell lines as well as encouraging antitumor activity in combination with other cytotoxic agents (Adams 2002;Escobar et al 2011;Okur and Yerlikaya 2019;Yerlikaya and Erin 2008). In fact, the 26S proteasome inhibitor bortezomib and carfilzomib are approved by the Food and Drug Administration (FDA) in 2003 and 2012, respectively, for the treatment of patients with relapsed and refractory multiple myeloma (MM) (Kane et al 2003;Thompson 2013).…”

Section: Introductionmentioning

confidence: 99%

An investigation of the mechanisms underlying the proteasome inhibitor bortezomib resistance in PC3 prostate cancer cell line

Yerlikaya¹,

Okur

2019

Cytotechnology

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The phenomenon of acquired resistance to chemotherapeutic agents is a long-standing conundrum in cancer treatment. To help delineate drug resistance mechanisms and pave the way for the development of novel strategies, we generated a PC3 prostate cancer cell line resistant to proteasome inhibitor bortezomib for the first time. The resistant cells were found to have an IC 50 value of 359.6 nM, whereas the IC 50 value of parental cells was 82.6 nM after 24 h of treatment with varying doses of bortezomib. The resistant cells were also partly crossresistant to the novel proteasome inhibitor carfilzomib; however, they were not resistant to widely used chemotherapeutic agent vincristine sulfate, indicating that enhanced cellular drug efflux via the multidrug resistance (MDR) transporters is not the molecular basis of the resistance. Since both bortezomib and carfilzomib target and inhibit the chymotrypsin-related activity residing in the b5 subunit of the proteasome (PSMB5), we next examined its expression and found surprisingly no significant alteration in the expression profile of the mature form. However, a significant increase in the accumulation of the precursor form of PSMB5 in response to 100 nM bortezomib was observed in the parental cells without a significant accumulation in the resistant cells. The results presented here thus suggest that the molecular mechanisms causing resistance to proteasome inhibitors need to be examined in-depth to overcome the resistance to ubiquitin-proteasome pathway inhibitors in cancer treatment.

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“…To further improve the anti-lymphoma activity of OTSSP167, in vitro combination studies were performed. Previously, studies in multiple myeloma and breast cancer demonstrated that combining OTSSP167 with standard-ofcare agents (including lenalidomide, pomalidomide, and bortezomib) could increase the anti-cancer effect of the standard-of-care agent 18,53 . A promising novel agent in clinical development in DLBCL and MCL is the selective Bcl-2 inhibitor venetoclax (also known as ABT-199).…”

Section: Discussionmentioning

confidence: 99%

Maternal embryonic leucine zipper kinase is a novel target for diffuse large B cell lymphoma and mantle cell lymphoma

Maes

Vlummens

et al. 2019

Blood Cancer J.

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Diffuse large B cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) are among the most aggressive B cell non-Hodgkin lymphomas. Maternal embryonic leucine zipper kinase (MELK) plays a role in cancer cell cycle progression and is associated with poor prognosis in several cancer cell types. In this study, the role of MELK in DLBCL and MCL and the therapeutic potential of MELK targeting is evaluated. MELK is highly expressed in DLBCL and MCL patient samples, correlating with a worse clinical outcome in DLBCL. Targeting MELK, using the small molecule OTSSP167, impaired cell growth and survival and induced caspase-mediated apoptosis in the lymphoma cells. Western blot analysis revealed that MELK targeting decreased the phosphorylation of FOXM1 and the protein levels of EZH2 and several mitotic regulators, such as Cdc25B, cyclin B1, Plk-1, and Aurora kinases. In addition, OTSSP167 also sensitized the lymphoma cells to the clinically relevant Bcl-2 inhibitor venetoclax by strongly reducing Mcl1 levels. Finally, OTSSP167 treatment of A20-inoculated mice resulted in a significant prolonged survival. In conclusion, targeting MELK with OTSSP167 induced strong anti-lymphoma activity both in vitro and in vivo. These findings suggest that MELK could be a potential new target in these aggressive B cell malignancies.

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A novel and effective inhibitor combination involving bortezomib and OTSSP167 for breast cancer cells in light of label-free proteomic analysis

Abstract: Altogether, the results presented here indicate that bortezomib + OTSSP167 is a novel and effective combination and may be tested further for cancer treatment in vivo and in clinical settings.

Cited by 9 publications

References 35 publications

Integrated multi-omics analysis of genomics, epigenomics, and transcriptomics in ovarian carcinoma

Integrated multi-omics analysis of genomics, epigenomics, and transcriptomics in ovarian carcinoma

An investigation of the mechanisms underlying the proteasome inhibitor bortezomib resistance in PC3 prostate cancer cell line

Maternal embryonic leucine zipper kinase is a novel target for diffuse large B cell lymphoma and mantle cell lymphoma

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