New Anti-Mitotic Drugs with Distinct Anti-Calmodulin Activity

Orosz, Ferenc; Horváth, István; Ovádi, Judit

doi:10.2174/138955706778560094

Cited by 12 publications

(5 citation statements)

References 52 publications

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“…Accordingly, new therapeutic strategies in oncology are being attempted. A new generation of anti-mitotic drugs has been produced that impede mitotic spindle assembly by specifically targeting CaM (104). Moreover, the human CaMKII inhibitory protein (hCaMKII␤), which is downregulated in ovarian cancer cells, has been found to decrease the tumorigenicity and growth of human ovarian cancer cells injected in mice by blocking cell cycle and stimulating apoptosis (81).…”

Section: Downstream Actions Of Ca 2ϩmentioning

confidence: 99%

Ion channels and transporters in cancer. 1. Ion channels and cell proliferation in cancer

Becchetti

2011

American Journal of Physiology-Cell Physiology

165

147

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Progress through the cell mitotic cycle requires precise timing of the intrinsic molecular steps and tight coordination with the environmental signals that maintain a cell into the proper physiological context. Because of their great functional flexibility, ion channels coordinate the upstream and downstream signals that converge on the cell cycle machinery. Both voltage- and ligand-gated channels have been implicated in the control of different cell cycle checkpoints in normal as well as neoplastic cells. Ion channels mediate the calcium signals that punctuate the mitotic process, the cell volume oscillations typical of cycling cells, and the exocytosis of autocrine or angiogenetic factors. Other functions of ion channels in proliferation are still matter of debate. These may or may not depend on ion transport, as the channel proteins can form macromolecular complexes with growth factor and cell adhesion receptors. Direct conformational coupling with the cytoplasmic regulatory proteins is also possible. Derangement or relaxed control of the above processes can promote neoplasia. Specific types of ion channels have turned out to participate in the different stages of the tumor progression, in which cell heterogeneity is increased by the selection of malignant cell clones expressing the ion channel types that better support unrestrained growth. However, a comprehensive mechanistic picture of the functional relations between ion channels and cell proliferation is yet not available, partly because of the considerable experimental challenges offered by studying these processes in living mammalian cells. No doubt, such studies will constitute one of the most fruitful research fields for the next generation of cell physiologists.

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Section: Downstream Actions Of Ca 2ϩmentioning

confidence: 99%

Ion channels and transporters in cancer. 1. Ion channels and cell proliferation in cancer

Becchetti

2011

American Journal of Physiology-Cell Physiology

165

147

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“…Inhibition of CaM has been thought to have potential therapeutic effects in cancer (49,50) because of its suppressing action on cell proliferation and/or their capacity to revert the multi-drug resistance tendency of many tumor cells (51)(52)(53)(54). A great variety of CaM antagonists have been described and their mechanisms of action established (55)(56)(57)(58)(59).…”

Section: Targeting Calmodulin In Cancermentioning

confidence: 99%

Targeting the Calmodulin-Regulated ErbB/Grb7 Signaling Axis in Cancer Therapy

et al. 2013

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Signal transduction pathways essential for the survival and viability of the cell and that frequently present aberrant expression or function in tumors are attractive targets for pharmacological intervention in human cancers. In this short review we will describe the regulation exerted by the calcium-receptor protein calmodulin (CaM) on signaling routes involving the family of ErbB receptors - highlighting the epidermal growth factor receptor (EGFR/ErbB1) and ErbB2 - and the adaptor protein Grb7, a downstream signaling component of these receptors. The signaling mechanism of the ErbB/Grb7 axis and the regulation exerted by CaM on this pathway will be described. We will present a brief overview of the current efforts to inhibit the hyperactivity of ErbB receptors and Grb7 in tumors. The currently available information on targeting the CaM-binding site of these signaling proteins will be analyzed, and the pros and cons of directly targeting CaM versus the CaM-binding domain of the ErbB receptors and Grb7 as potential anti-cancer therapy will be discussed. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

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“…Therefore, future research should focus on exploring more biomarkers to optimize the therapeutic effect on EGFR inhibitors. CALM inhibitors plays an essential role in cell proliferation and/or reverse multiple drug resistance tendencies in many tumor cells [41,42], so it has been thought it has potential therapeutic effects in cancer [43,44]. Based on many studies which mostly performed in vitro point to a potential benefit of treating cancers with CALM antagonists.…”

Section: Discussionmentioning

confidence: 99%

CALM1 promotes progression and dampens chemosensitivity to EGFR inhibitor in esophageal squamous cell carcinoma

Liu¹,

Han²,

Liu³

et al. 2021

Preprint

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Background: Calmodulin1 (CALM1) has been identified as one of the overexpression genes in a variety of cancers and EGFR inhibitor have been widely used in clinical treatment but it is unknown whether CALM1 and epidermal growth factor receptor (EGFR) have a synergistic effect in esophageal squamous cell carcinoma (ESCC). The aim of the present study was to explore the synergistic effects of knock-out CALM1 combined with EGFR inhibitor (Afatinib) and to elucidate the role of CALM1 in sensitizing the resistance to Afatinib in ESCC. Method: Immunohistochemistry (IHC) and qRT-PCR were used to examine the expression of CALM1 and EGFR in ESCC tissues. Kaplan–Meier survival analysis was used to analyze the clinical and prognostic significance of CALM1 and EGFR expression in ESCC. Furthermore, to evaluate the biological function of CALM1 in ESCC, the latest gene editing technique CRISPR/Cas9（Clustered regularly interspaced short palindromic repeats）was applied to knockout CALM1 in ESCC cell lines KYSE150, Eca109 and TE-1. MTT, flow cytometry, Transwell migration, scratch wound-healing and colony formation assays were performed to assay the combined effect of knock-out CALM1 and EGFR inhibitor on ESCC cell proliferation and migration. In addition, nude mice xenograft model was used to observe the synergistic inhibition of knock-out CALM1 and Afatinib.Results: Both CALM1 and EGFR were found to be significantly over-expressed in ESCC compared with paired normal control. Over-expressed CALM1 and EGFR were significantly associated with clinical stage, T classification and poor overall prognosis, respectively. In vitro, the combined effect of knock-out CALM1 mediated by the lentivirus and EGFR inhibitor was shown to be capable of inhibiting the proliferation, inducing cell cycle arrest at G1/S stage and increasing apoptosis of KYSE-150 and Eca109 cells; invasion and migration were also suppressed. In vivo, the results of tumor weight and total fluorescence were markedly reduced compared with the sgCtrl-infected group and sgCAML1 group.Conclusion: Our data demonstrated that knock-out of CALM1 could sensitize ESCC cells to EGFR inhibitor, and it may exert oncogenic role via promotion of EMT. Taken together, CALM1 may be a tempting target to overcome Afatinib resistance.

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New Anti-Mitotic Drugs with Distinct Anti-Calmodulin Activity

Cited by 12 publications

References 52 publications

Ion channels and transporters in cancer. 1. Ion channels and cell proliferation in cancer

Ion channels and transporters in cancer. 1. Ion channels and cell proliferation in cancer

Targeting the Calmodulin-Regulated ErbB/Grb7 Signaling Axis in Cancer Therapy

CALM1 promotes progression and dampens chemosensitivity to EGFR inhibitor in esophageal squamous cell carcinoma

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