Synthesis of microtubule-interfering halogenated noscapine analogs that perturb mitosis in cancer cells followed by cell death

Aneja, Ritu; Vangapandu, Surya N.; Lopus, Manu; Viswesarappa, Vijaya G.; Dhiman, Neerupma; Verma, Akhilesh K.; Chandra, Ramesh; Panda, Dulal; Joshi, Harish C.

doi:10.1016/j.bcp.2006.05.004

Cited by 90 publications

(117 citation statements)

References 42 publications

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“…It was also demonstrated that triple-negative cells MDA-MB-231 was more sensitive than triple-positive MCF-7 cells in treatment with noscapine which agrees with the results of other studies (21,22). Noscapine provides promise as an effective anticancer agent with lower toxicity on normal cells.…”

Section: Discussionsupporting

confidence: 80%

Apoptotic effect of noscapine in breast cancer cell lines

Quisbert-Valenzuela

Calaf

2016

International Journal of Oncology

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Abstract. Cancer is a public health problem in the world and breast cancer is the most frequently cancer in women. Approximately 15% of the breast cancers are triple-negative. Apoptosis regulates normal growth, homeostasis, development, embryogenesis and appropriate strategy to treat cancer. Bax is a protein pro-apoptotic enhancer of apoptosis in contrast to Bcl-2 with antiapoptotic properties. Initiator caspase-9 and caspase-8 are features of intrinsic and extrinsic apoptosis pathway, respectively. NF-κB is a transcription factor known to be involved in the initiation and progression of breast cancer. Noscapine, an alkaloid derived from opium is used as antitussive and showed antitumor properties that induced apoptosis in cancer cell lines. The aim of the present study was to determine the apoptotic effect of noscapine in breast cancer cell lines compared to breast normal cell line. Three cell lines were used: i) a control breast cell line MCF-10F; ii) a luminallike adenocarcinoma triple-positive breast cell line MCF-7; iii) breast cancer triple-negative cell line MDA-MB-231. Our results showed that noscapine had lower toxicity in normal cells and was an effective anticancer agent that induced apoptosis in breast cancer cells because it increases Bax gene and protein expression in three cell lines, while decreases Bcl-xL gene expression, and Bcl-2 protein expression decreased in breast cancer cell lines. Therefore, Bax/Bcl-2 ratio increased in the three cell lines. This drug increased caspase-9 gene expression in breast cancer cell lines and caspase-8 gene expression increased in MCF-10F and MDA-MB-231. Furthermore, it increased cleavage of caspase-8, suggesting that noscapineinduced apoptosis is probably due to the involvement of extrinsic and intrinsic apoptosis pathways. Antiapoptotic gene and protein expression diminished and proapoptotic gene and protein expression increased noscapine-induced expression, probably due to decrease in NF-κB gene and protein expression and also by increase of IκBα gene expression induced by this drug. IntroductionCancer is a leading cause of death in both more and less economically developed countries; the burden is expected to grow worldwide due to the growth and aging of the population and improvements in early detection and treatment (1). Cancer is a major public health problem in many parts of the world. It is currently the second leading cause of death in the United States (1,2). Breast cancer, is the most frequently occurring cancer in women and some cases show slow growth with excellent prognosis, while aggressive tumors have poor prognosis (1-3). Breast tumors have also been identified into different subtypes based on the expression of estrogen receptors (ER), progesterone receptors (PR) and Her2 oncogene. The breast tumors that do not express ER, PR or Her2 are called triple-negative breast cancers and ~15% of the breast cancers fall into this category (3,4).Apoptosis is a process of programmed cell death that occurs in response to environmental stimuli and normal gro...

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Section: Discussionsupporting

confidence: 80%

Apoptotic effect of noscapine in breast cancer cell lines

Quisbert-Valenzuela

Calaf

2016

International Journal of Oncology

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“…Reaction mixture was stirred at room temperature for 1 h and neutralized with ammonia solution to ph 10.0 to obtain a solid precipitate of reduced 9-bromo-noscapine (5) to obtain reduced 9-azido-noscapine (6), compound 5 was used as the starting material, and a parallel procedure was followed as described above for the synthesis of 9-azido-noscapine (3). Yield for compound 6 …”

Section: Synthesis Of Reduced 9-azido-noscapine [((S)-3-((r)-9-azido-mentioning

confidence: 99%

Rational Design of Novel Anti-microtubule Agent (9-Azido-Noscapine) from Quantitative Structure Activity Relationship (QSAR) Evaluation of Noscapinoids

2011

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An anticough medicine, noscapine [(S)-3-((R)4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)-6,7-dimethoxyiso-benzofuran-1(3H)-one], was discovered in the authors’ laboratory as a novel type of tubulin-binding agent that mitigates polymerization dynamics of microtubule polymers without changing overall subunit-polymer equilibrium. To obtain systematic insight into the relationship between the structural framework of noscapine scaffold and its antitumor activity, the authors synthesized strategic derivatives (including two new ones in this article). The IC50 values of these analogs vary from 1.2 to 56.0 µM in human acute lymphoblastic leukemia cells (CEM). Geometrical optimization was performed using semiempirical quantum chemical calculations at the 3-21G* level. Structures were in agreement with nuclear magnetic resonance analysis of molecular flexibility in solution and crystal structures. A genetic function approximation algorithm of variable selection was used to generate the quantitative structure activity relationship (QSAR) model. The robustness of the QSAR model ( R2 = 0.942) was analyzed by values of the internal cross-validated regression coefficient ( R2LOO = 0.815) for the training set and determination coefficient ( R2test = 0.817) for the test set. Validation was achieved by rational design of further novel and potent antitumor noscapinoid, 9-azido-noscapine, and reduced 9-azido-noscapine. The experimentally determined value of pIC50 for both the compounds (5.585 M) turned out to be very close to predicted pIC50 (5.731 and 5.710 M).

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“…We have shown that EM011 is a potent anticancer agent that briefly arrests a wide variety of cancer cell types in the G 2 -M phase of the cell cycle followed by abortive mitoses, which, in turn, activate a mitochondrially driven apoptotic program leading to cancer cell death (14,15). We have also shown earlier that noscapinoids arrest normal cells too at mitoses but they resume normal cell cycle after the drug is removed or cleared from the system (16).…”

Section: Introductionmentioning

confidence: 95%

Nonimmunosuppressive chemotherapy: EM011-treated mice mount normal T-cell responses to an acute lymphocytic choriomeningitis virus infection

Aneja

Kalia

Ahmed

et al. 2007

Molecular Cancer Therapeutics

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Myelosuppression and associated immunosuppression are major problems in cancer chemotherapy. Thus, infection remains a significant source of morbidity and mortality during chemotherapy of cancer patients. Viral infections, particularly herpes simplex virus, varicella zoster virus, and cytomegalovirus, result either due to reactivation of latent viruses or new infections as sequelae of chemotherapy and debilitated cell-mediated immunity. Ultimately, the resolution of these infections can only be achieved after the control of malignancy and regaining the patient's ability to mount adequate immune responses. We show here that EM011, a tubulin-binding, nontoxic, orally available anticancer agent, does not alter absolute CD4 + , CD8 + , B220 + , and NK1

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Synthesis of microtubule-interfering halogenated noscapine analogs that perturb mitosis in cancer cells followed by cell death

Cited by 90 publications

References 42 publications

Apoptotic effect of noscapine in breast cancer cell lines

Apoptotic effect of noscapine in breast cancer cell lines

Rational Design of Novel Anti-microtubule Agent (9-Azido-Noscapine) from Quantitative Structure Activity Relationship (QSAR) Evaluation of Noscapinoids

Nonimmunosuppressive chemotherapy: EM011-treated mice mount normal T-cell responses to an acute lymphocytic choriomeningitis virus infection

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