Ellipticine derivative NSC 338258 represents a potential new antineoplastic agent for the treatment of multiple myeloma

Tian, Erming; Landowski, Terry H.; Stephens, Owen; Yaccoby, Shmuel; Barlogie, Bart; Shaughnessy, John D.

doi:10.1158/1535-7163.mct-07-0524

Cited by 17 publications

(14 citation statements)

References 26 publications

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“…23 Another ellipticine derivative NSC338258 was shown to exhibit cytotoxicity in myeloma cells independent of topoisomerase II inhibition. 24 These studies are consistent with our findings and suggest that a close derivative to ellipticine might act by different mechanisms to suppress tumors.…”

Section: Resultssupporting

confidence: 92%

“…Resistance of p53-mutant or -null tumors to conventional radiation and activate the mitochondrial apoptotic pathway. 24 Interestingly, studies have shown that ellipticine has the ability to restore mutant p53 function. An analysis has indicated that ellipticine and its analogs were more potent against cell lines that harbor mutant p53 in growth inhibition assays.…”

Section: Discussionmentioning

confidence: 99%

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Non-genotoxic anti-neoplastic effects of ellipticine derivative NSC176327 in p53-deficient human colon carcinoma cells involve stimulation of p73

Lü

Wang²,

El‐Deiry³

2008

Cancer Biology & Therapy

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We previously performed a high-throughput screen using real-time noninvasive bioluminescence imaging of p53 transcriptional activity and identified a group of small molecules that trigger p53-like transcriptional responses in p53-deficient tumor cells. Here we further examined the anti-tumor effects of selected compounds in vitro and showed that NSC176327, a derivative of the cytotoxic plant alkaloid ellipticine, exhibited strong anti-neoplastic effect sin wild-type p53, p53-mutant or p53-deficient human colon cancer cells. NSC176327 was more potent at inhibiting tumor cell growth as compared to chemotherapeutic drugs and other ellipticine derivatives and induced cell cycle arrest and apoptosis. Surprisingly, unlike what is observed with the parent compound ellipticine, a DNA damage signaling response was not observed with NSC176327 as evidenced by lack of phosphorylated histone H2AX foci in NSC176327-treated tumor cells. NSC176327 treatment caused a significant increase in p53-activated reporter signal in HCT116, SW620 and HCT116 p53-/- cells and upregulated DR5 and p21 protein expression. NSC176327 treatment also resulted in increased p73 protein expression and knockdown of transactivating isoforms of p73 in HCT116 p53-/- cells showed significant resistance to drug treatment. These results demonstrate an important role of p73 in the anti-tumor effects of NSC176327,and suggest that a close analogue of ellipticine may act by a non-genotoxic mechanism targeting the p53/p73 pathway as compared to the original parent compound that targets the same pathway.

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Section: Resultssupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Non-genotoxic anti-neoplastic effects of ellipticine derivative NSC176327 in p53-deficient human colon carcinoma cells involve stimulation of p73

Lü

Wang²,

El‐Deiry³

2008

Cancer Biology & Therapy

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“…DT204 has been shown to reduce myeloma viability by inducing cell cycle arrest and enhancing the anti-myeloma effect of BTZ in MM cell lines and patient samples [64]. Recently, using the COMPARE algorithm to identify the correlation between CKS1B gene expression and drug activity, Tian et al identified 9-dimethyl amino-ethoxy ellipticine (EPED3), a highly stable compound derivative of the plant alkaloid ellipticine [65]. Studies using MM cells showed that treatment with EPED3 induced cell death.…”

Section: Cks1bmentioning

confidence: 99%

Role of 1q21 in Multiple Myeloma: From Pathogenesis to Possible Therapeutic Targets

Burroughs‐Garcia

Eufemiese

Storti

et al. 2021

Cells

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Multiple myeloma (MM) is characterized by an accumulation of malignant plasma cells (PCs) in the bone marrow (BM). The amplification of 1q21 is one of the most common cytogenetic abnormalities occurring in around 40% of de novo patients and 70% of relapsed/refractory MM. Patients with this unfavorable cytogenetic abnormality are considered to be high risk with a poor response to standard therapies. The gene(s) driving amplification of the 1q21 amplicon has not been fully studied. A number of clear candidates are under investigation, and some of them (IL6R, ILF2, MCL-1, CKS1B and BCL9) have been recently proposed to be potential drivers of this region. However, much remains to be learned about the biology of the genes driving the disease progression in MM patients with 1q21 amp. Understanding the mechanisms of these genes is important for the development of effective targeted therapeutic approaches to treat these patients for whom effective therapies are currently lacking. In this paper, we review the current knowledge about the pathological features, the mechanism of 1q21 amplification, and the signal pathway of the most relevant candidate genes that have been suggested as possible therapeutic targets for the 1q21 amplicon.

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“…Thus, CKS1B amplification may indicate aggressive clinical behavior. Interestingly, some drugs, such as fluoxetine and EPED3, have been reported to have a specific anti-CKS1B activity leading to an antiproliferative tumor cell activity (Krishnan et al, 2008;Tian et al, 2008). The future potential of these therapeutic drugs in the management of malignant neoplasms presenting CKS1B amplification and/or overexpression has to be defined.…”

Section: Cks1b In Cutaneous Squamous Cell Carcinomamentioning

confidence: 99%

CKS1B amplification is a frequent event in cutaneous squamous cell carcinoma with aggressive clinical behaviour

Salgado

Toll

Alameda

et al. 2010

Genes Chromosomes & Cancer

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Genetic mechanisms giving rise to the development of cutaneous squamous cell carcinoma (cSCC) are poorly understood and development of genomic high resolution techniques has led to a better knowledge of the genetic basis of several human cancers. In this study, 16 cSCC were analyzed using array comparative genomic hybridization (arrayCGH). The most common aberrations found were gains of 3q11q13, 1q21.3q25, 13q34, and 19p13, and losses of 1p36p31, 3p24p21, 10p15q22, and 13q11q21. We detected gains (3/16) and amplification (1/16) of the 1q21.1q21.3 region. A potential candidate gene in this region, CKS1B (1q21.2), was selected for validation in an independent cohort and correlations with clinicopathological features were carried out. CKS1B gene and protein status were analyzed using fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) in a series of 53 cSCC, 22 actinic keratoses (AK), and 10 normal skin samples. cSCC presented a higher frequency of chromosome 1 polysomy than AK (70% vs. 46%, P = 0.047). Association between CKS1B protein overexpression and both polysomy and amplification was demonstrated in cSCC (P < 0.001). Regarding amplifications, 11 cSCC patients (21%) presented CKS1B gene amplification. Interestingly, 8/11 (73%) patients who showed a CKS1B amplification had presented metastatic spread (mcSCC). Differences between the presence of CKS1B amplification and the presence or absence of mcSCC were observed (mcSCC [8/14] vs. cSCC [3/39]) (P < 0.001). Several drugs targeting CKS1B have been reported and may be useful for treating patients with cSCC and CKS1B amplifications.

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Ellipticine derivative NSC 338258 represents a potential new antineoplastic agent for the treatment of multiple myeloma

Abstract: High-risk multiple myeloma can be correlated with amplification and overexpression of the cell cycle regulator CKS1B. Herein, we used the COMPARE algorithm to correlate high expression of CKS1B mRNA in the NCI-60 cell line panel with the concentration causing 50% growth inhibition (GI 50

Cited by 17 publications

References 26 publications

Non-genotoxic anti-neoplastic effects of ellipticine derivative NSC176327 in p53-deficient human colon carcinoma cells involve stimulation of p73

Non-genotoxic anti-neoplastic effects of ellipticine derivative NSC176327 in p53-deficient human colon carcinoma cells involve stimulation of p73

Role of 1q21 in Multiple Myeloma: From Pathogenesis to Possible Therapeutic Targets

CKS1B amplification is a frequent event in cutaneous squamous cell carcinoma with aggressive clinical behaviour

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