Anti-Cancer Activity of Curcumin on Multiple Myeloma

2020 ◽  
Vol 20 ◽  
Author(s):  
Hamed Mirzaei ◽  
Hossein Bagheri ◽  
Faezeh Ghasemi ◽  
Jaber M. Khoi ◽  
Mohammad H. Pourhanifeh ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Multiple Myeloma ◽  
Signaling Pathways ◽  
Wide Spectrum ◽  
Curcuma Longa ◽  
Bone Lesion ◽  
Cell Cycle Checkpoint ◽  
Cell Cycle Checkpoints ◽  
Cycle Checkpoint ◽  
Therapeutic Properties

: Multiple Myeloma (MM) is the third most common and deadly hematological malignancy, which is characterized by a progressive monoclonal proliferation within the bone marrow. MM is cytogenetically heterogeneous with numerous genetic and epigenetic alterations, which lead to a wide spectrum of signaling pathways and cell cycle checkpoint aberrations. MM symptoms can be attributed to CRAB features (hyperCalcemia, Renal failure, Anemia and Bone lesion), which profoundly affect both the Health-Related Quality of Life (HRQoL) and the life expectancy of patients. Despite all enhancement and improvement in therapeutic strategies, MM is almost incurable, and patients faced to this disease eventually relapse. Curcumin is an active and nontoxic phenolic compound, isolated from the rhizome of Curcuma longa L. It has been widely studied and has a confirmed broad range of therapeutic properties, especially anticancer activity, including anti-proliferation, anti-angiogenesis, antioxidant and anti-mutation activities. Curcumin induces apoptosis in cancerous cells and prevents Multidrug Resistance (MDR). Growing evidence concerning the therapeutic properties of curcumin caused a pharmacological impact on MM. It is confirmed that curcumin interferes with various signaling pathways and cell cycle checkpoints, and with oncogenes. In this paper, we summarized the anti-MM effects of curcumin.

Molecular analyses of adaptive survival responses (ASRs): role of ASRs in radiotherapy

1998 ◽  
Vol 17 (8) ◽  
pp. 448-453 ◽  
Author(s):  
David A Boothman ◽  
Eric Odegaard ◽  
Chin-Rang Yang ◽  
Kelly Hosley ◽  
Marc S Mendonca
Keyword(s):  
Cell Cycle ◽  
Stress Responses ◽  
Strand Break ◽  
Cell Cycle Checkpoint ◽  
Cell Cycle Checkpoints ◽  
Specific Gene ◽  
High Dose ◽  
Neoplastic Cells ◽  
Normal Cells ◽  
Cycle Checkpoint

Adaptive survival responses (ASRs), whereby cells demonstrate a survival advantage when exposed to very low doses of ionizing radiation (IR) 4-24 h prior to a high dose challenge, were first reported over 15 years ago. These responses were linked to hormesis, which implied that exposure to low levels of IR may be beneficial to the cell. We postulate that increased survival does not necessarily mean that the treatment is beneficial.Studies at the molecular level indicate that ASRs are the result of misregulated cell cycle checkpoint responses, occurring in the G1 phase of the cell cycle after IR. Specific gene products (i.e., PCNA, cyclin D1, cyclin A, XIP8, xip5 and xip13) appear to control these cell cycle checkpoint responses. Certain neoplastic cells show potent ASRs because they bypass checkpoints which would otherwise lead to apoptosis or other forms of cell death (possibly necrosis), and/or these cancer cells lack genetic factors, such as specific caspases (cysteine aspartate-specific proteases), that control apoptosis. Alterations in these cell cycle checkpoints or apoptotic responses may also occur during IR-induced stress responses in normal cells, at critical times (10-18 days posttreatment) following IR. One IR-induced protein, XIP8, may be a critical controlling factor at this point where delayed-onset apoptosis occurs. Additionally, we have shown that the presence or absence (i.e., SCID cells) of nonhomologous DNA double strand break repair did not seem to influence ASRs, suggesting that ASRs may be caused by signal transduction stress responses.ASRs may be beneficial to survival, however, the consequence(s) of that survival may be dire. For example, many neoplastic cells exhibited far greater ASRs than normal cells. Additionally, ASRs were induced by as little as 1 cGy and and were enhanced by repeated exposures of low level radiation. The implications for radiotherapy are that when a patient arrives for port film imaging during the course of therapy, the dose-rate, overall level of exposure, and time between port film exposure and high dose IR treatment become potentially important factors for improved efficacy of treatment of certain cancers. Further research is warranted to determine what molecular factors are most important for ASRs, and current work is focusing on XIP8.

Abstract 1884: Dual targeting of cell cycle checkpoint and histone deacetylase overcomes bortezomib resistance in multiple myeloma

2018 ◽  
Author(s):  
Takayuki Tabayashi ◽  
Yuka Tanaka ◽  
Yasuyuki Takahashi ◽  
Yuta Kimura ◽  
Tatsuki Tomikawa ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Multiple Myeloma ◽  
Histone Deacetylase ◽  
Cell Cycle Checkpoint ◽  
Dual Targeting ◽  
Cycle Checkpoint

scholarly journals Negative regulator of E2F transcription factors links cell cycle checkpoint and DNA damage repair

2018 ◽  
Vol 115 (16) ◽  
pp. E3837-E3845 ◽  
Author(s):  
Lili Wang ◽  
Hanchen Chen ◽  
Chongyang Wang ◽  
Zhenjie Hu ◽  
Shunping Yan
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Dna Repair ◽  
Transcription Factors ◽  
Genome Stability ◽  
Cell Cycle Checkpoint ◽  
Cell Cycle Checkpoints ◽  
Negative Regulator ◽  
Cycle Checkpoint ◽  
E2f Transcription Factors

DNA damage poses a serious threat to genome integrity and greatly affects growth and development. To maintain genome stability, all organisms have evolved elaborate DNA damage response mechanisms including activation of cell cycle checkpoints and DNA repair. Here, we show that the DNA repair protein SNI1, a subunit of the evolutionally conserved SMC5/6 complex, directly links these two processes in Arabidopsis. SNI1 binds to the activation domains of E2F transcription factors, the key regulators of cell cycle progression, and represses their transcriptional activities. In turn, E2Fs activate the expression of SNI1, suggesting that E2Fs and SNI1 form a negative feedback loop. Genetically, overexpression of SNI1 suppresses the phenotypes of E2F-overexpressing plants, and loss of E2F function fully suppresses the sni1 mutant, indicating that SNI1 is necessary and sufficient to inhibit E2Fs. Altogether, our study revealed that SNI1 is a negative regulator of E2Fs and plays dual roles in DNA damage responses by linking cell cycle checkpoint and DNA repair.

scholarly journals Heterogeneities in Cell Cycle Checkpoint Activation Following Doxorubicin Treatment Reveal Targetable Vulnerabilities in TP53 Mutated Ultra High-Risk Neuroblastoma Cell Lines

2021 ◽  
Vol 22 (7) ◽  
pp. 3664
Author(s):  
Linnéa Ödborn Jönsson ◽  
Maryam Sahi ◽  
Ximena Lopez-Lorenzo ◽  
Faye Leilah Keller ◽  
Ourania N. Kostopoulou ◽  
...  
Keyword(s):  
Cell Cycle ◽  
High Risk ◽  
Cell Lines ◽  
Neuroblastoma Cell ◽  
Cell Cycle Checkpoint ◽  
Cell Cycle Checkpoints ◽  
Dna Integrity ◽  
Checkpoint Activation ◽  
Ultra High Risk ◽  
Cycle Checkpoint

Most chemotherapeutics target DNA integrity and thereby trigger tumour cell death through activation of DNA damage responses that are tightly coupled to the cell cycle. Disturbances in cell cycle regulation can therefore lead to treatment resistance. Here, a comprehensive analysis of cell cycle checkpoint activation following doxorubicin (doxo) treatment was performed using flow cytometry, immunofluorescence and live-cell imaging in a panel of TP53 mutated ultra high-risk neuroblastoma (NB) cell lines, SK-N-DZ, Kelly, SK-N-AS, SK-N-FI, and BE(2)-C. Following treatment, a dose-dependent accumulation in either S- and/or G2/M-phase was observed. This coincided with a heterogeneous increase of cell cycle checkpoint proteins, i.e., phos-ATM, phos-CHK1, phos-CHK2, Wee1, p21Cip1/Waf1, and p27Kip among the cell lines. Combination treatment with doxo and a small-molecule inhibitor of ATM showed a delay in regrowth in SK-N-DZ, of CHK1 in BE(2)-C, of Wee1 in SK-N-FI and BE(2)-C, and of p21 in Kelly and BE(2)-C. Further investigation revealed, in all tested cell lines, a subset of cells arrested in mitosis, indicating independence on the intra-S- and/or G2/M-checkpoints. Taken together, we mapped distinct cell cycle checkpoints in ultra high-risk NB cell lines and identified checkpoint dependent and independent druggable targets.

scholarly journals WEE1 Inhibition Enhances Anti-Apoptotic Dependency as a Result of Premature Mitotic Entry and DNA Damage

Cancers ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 1743 ◽  
Author(s):  
Mathilde Rikje Willemijn de Jong ◽  
Myra Langendonk ◽  
Bart Reitsma ◽  
Pien Herbers ◽  
Marcel Nijland ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
B Cell Lymphoma ◽  
Cell Cycle Checkpoint ◽  
Cell Cycle Checkpoints ◽  
Specific Cell ◽  
M Cell ◽  
Mitotic Entry ◽  
Enhanced Sensitivity ◽  
Cycle Checkpoint

Genomically unstable cancers are dependent on specific cell cycle checkpoints to maintain viability and prevent apoptosis. The cell cycle checkpoint protein WEE1 is highly expressed in genomically unstable cancers, including diffuse large B-cell lymphoma (DLBCL). Although WEE1 inhibition effectively induces apoptosis in cancer cells, the effect of WEE1 inhibition on anti-apoptotic dependency is not well understood. We show that inhibition of WEE1 by AZD1775 induces DNA damage and pre-mitotic entry in DLBCL, thereby enhancing dependency on BCL-2 and/or MCL-1. Combining AZD1775 with anti-apoptotic inhibitors such as venetoclax (BCL-2i) or S63845 (MCL-1i) enhanced sensitivity in a cell-specific manner. In addition, we demonstrate that both G2/M cell cycle arrest and DNA damage induction put a similar stress on DLBCL cells, thereby enhancing anti-apoptotic dependency. Therefore, genotoxic or cell cycle disrupting agents combined with specific anti-apoptotic inhibitors may be very effective in genomic unstable cancers such as DLBCL and therefore warrants further clinical evaluation.

scholarly journals The Aspergillus nidulans snt Genes Are Required for the Regulation of Septum Formation and Cell Cycle Checkpoints

Genetics ◽  
2001 ◽  
Vol 159 (2) ◽  
pp. 557-569
Author(s):  
Peter R Kraus ◽  
Steven D Harris
Keyword(s):  
Cell Cycle ◽  
Aspergillus Nidulans ◽  
Nuclear Division ◽  
Threshold Level ◽  
Cell Cycle Checkpoint ◽  
Cell Cycle Checkpoints ◽  
Gene Encoding ◽  
Temporal Regulation ◽  
Septum Formation ◽  
Cycle Checkpoint

Abstract In Aspergillus nidulans, germinating conidia undergo multiple rounds of nuclear division before forming a septum. Previous genetic results suggest that the ability to separate nuclear division and septum formation depends upon a threshold level of activity of the cyclin-dependent kinase NIMXcdk1. Mutations in nimX and nimT, the gene encoding the NIMXcdk1-activating phosphatase, have revealed that Tyr-15 phosphorylation is important for determining the timing of the formation of the first septum. Here, we describe a screen for suppressors of nimT23 (snt), designed to identify additional components of the pathway regulating septum formation. We show that a subset of the snt mutants are defective in the temporal regulation of septum formation and in cell cycle checkpoint responses. Molecular characterization of sntA shows that it is allelic to the previously described ankA gene, which encodes the NIMXcdk1 Tyr-15 kinase. Additional experiments described in this study show that nutritional conditions modulate the timing of septum formation and alter the phenotypes displayed by the snt mutants. A model that suggests that the timing of septum formation is influenced by DNA damage and glucose availability via the sntA and sntB gene products is proposed.

scholarly journals Two Molecularly Distinct G2/M Checkpoints Are Induced by Ionizing Irradiation

2002 ◽  
Vol 22 (4) ◽  
pp. 1049-1059 ◽  
Author(s):  
Bo Xu ◽  
Seong-Tae Kim ◽  
Dae-Sik Lim ◽  
Michael B. Kastan
Keyword(s):  
Cell Cycle ◽  
Mammalian Cells ◽  
S Phase ◽  
Cell Cycle Checkpoint ◽  
Cell Cycle Checkpoints ◽  
Ionizing Irradiation ◽  
Mammalian Cell Cycle ◽  
Cycle Checkpoint ◽  
Dose Dependent ◽  
S Phase Checkpoint

ABSTRACT Cell cycle checkpoints are among the multiple mechanisms that eukaryotic cells possess to maintain genomic integrity and minimize tumorigenesis. Ionizing irradiation (IR) induces measurable arrests in the G1, S, and G2 phases of the mammalian cell cycle, and the ATM (ataxia telangiectasia mutated) protein plays a role in initiating checkpoint pathways in all three of these cell cycle phases. However, cells lacking ATM function exhibit both a defective G2 checkpoint and a prolonged G2 arrest after IR, suggesting the existence of different types of G2 arrest. Two molecularly distinct G2/M checkpoints were identified, and the critical importance of the choice of G2/M checkpoint assay was demonstrated. The first of these G2/M checkpoints occurs early after IR, is very transient, is ATM dependent and dose independent (between 1 and 10 Gy), and represents the failure of cells which had been in G2 at the time of irradiation to progress into mitosis. Cell cycle assays that can distinguish mitotic cells from G2 cells must be used to assess this arrest. In contrast, G2/M accumulation, typically assessed by propidium iodide staining, begins to be measurable only several hours after IR, is ATM independent, is dose dependent, and represents the accumulation of cells that had been in earlier phases of the cell cycle at the time of exposure to radiation. G2/M accumulation after IR is not affected by the early G2/M checkpoint and is enhanced in cells lacking the IR-induced S-phase checkpoint, such as those lacking Nbs1 or Brca1 function, because of a prolonged G2 arrest of cells that had been in S phase at the time of irradiation. Finally, neither the S-phase checkpoint nor the G2 checkpoints appear to affect survival following irradiation. Thus, two different G2 arrest mechanisms are present in mammalian cells, and the type of cell cycle checkpoint assay to be used in experimental investigation must be thoughtfully selected.

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