Microtubules as a Target in Cancer Therapy

Risinger, April L.; Mooberry, Susan L.

doi:10.1007/978-1-61779-788-0_11

Cited by 4 publications

(5 citation statements)

References 99 publications

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“…Epothilones A and B were initially found in mycobacterium sorangrum cellulosum as cytotoxic metabolites that stabilize microtubules. Epothilones show higher cytotoxicity than taxanes in vitro [ 63 ]. For example, epothilone B shows a higher cytotoxicity to human ovarian cancer cells (OV-90) when compared to paclitaxel [ 64 ].…”

Section: Classes Of Antimitotic Drugsmentioning

confidence: 99%

“…Ixabepilone (Ixempra ® ) is a lactam analog of epothilone B (Table 1 ) [ 63 ]. The compound was approved by the USA in 2007 for use in the treatment of metastatic or locally advanced breast cancer that is resistant to taxanes and anthracycline [ 65 ].…”

Section: Classes Of Antimitotic Drugsmentioning

confidence: 99%

“…The agent was the first epothilone to be approved for clinical use. Ixabepilone is metabolically more stable than its precursor, epothilone B, and thus the most clinically advanced epothilone with regards to its efficacy and tolerability in breast cancer patients [ 63 ]. Ixabepilone cytotoxicity is decreased cell lines expressing P-glycoprotein (P-gp), namely Madin-Darby canine kidney cells transfected with the human multidrug resistance 1 gene (MDCK-MDR1) and pig kidney epithelial cells transfected with the human multidrug resistance 1 gene (LLCPK-MDR1) [ 66 ].…”

Section: Classes Of Antimitotic Drugsmentioning

confidence: 99%

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Antimitotic drugs in the treatment of cancer

Vuuren

Visagie

Theron

et al. 2015

Cancer Chemother Pharmacol

155

119

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Cancer is a complex disease since it is adaptive in such a way that it can promote proliferation and invasion by means of an overactive cell cycle and in turn cellular division which is targeted by antimitotic drugs that are highly validated chemotherapy agents. However, antimitotic drug cytotoxicity to non-tumorigenic cells and multiple cancer resistance developed in response to drugs such as taxanes and vinca alkaloids are obstacles faced in both the clinical and basic research field to date. In this review, the classes of antimitotic compounds, their mechanisms of action and cancer cell resistance to chemotherapy and other limitations of current antimitotic compounds are highlighted, as well as the potential of novel 17-β estradiol analogs as cancer treatment.

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Section: Classes Of Antimitotic Drugsmentioning

confidence: 99%

Section: Classes Of Antimitotic Drugsmentioning

confidence: 99%

Section: Classes Of Antimitotic Drugsmentioning

confidence: 99%

See 1 more Smart Citation

Antimitotic drugs in the treatment of cancer

Vuuren

Visagie

Theron

et al. 2015

Cancer Chemother Pharmacol

155

119

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“…The complexity entailed in MT instability is essential to the biological functions that MTs perform during cell division, migration, and intracellular trafficking [Piehl and Cassimeris, 2003; Etienne-Manneville, 2013]. Because of their central role in mitosis and cell migration, MTs provide an attractive target for chemotherapy against rapidly growing tumg tumors of the breast, ovary and lung [Honore et al ., 2005; Pasquier and Kavallaris, 2008; Risinger and Mooberryor cells such as in lymphoma and leukemia, metastatic cancers, and slow growin, 2012]. …”

Section: Introductionmentioning

confidence: 99%

Phosphorylation of α‐tubulin by protein kinase C stimulates microtubule dynamics in human breast cells

Tsimounis

Chen

et al. 2014

Cytoskeleton

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Protein kinase C (PKC) engenders motility through phosphorylation of α-tubulin at Ser-165 in non-transformed MCF-10A cells. Live cell imaging explored the impact of PKC-mediated phosphorylation on microtubule (MT) dynamics. MTs fluorescently labeled with GFP-α-tubulin were treated with diacylglycerol (DAG)-lactone (a membrane-permeable PKC activator), or co-transfected with a pseudo-phosphorylated S165D-α6-tubulin mutant. Each condition increased the dynamicity of MTs by stimulating the rate and duration of the growth phase and decreasing the frequency of catastrophe. In MDA-MB-231 metastatic breast cells where the intrinsic PKC activity is high, these MT growth parameters were also high but could be suppressed by expression of phosphorylation-resistant S165N-α6-tubulin or by treatment with a pan-PKC inhibitor (bis-indoleylmaleimide). Sub-cellular fractionation and immunofluorescence of MCF-10A cells showed that phosphorylation (via DAG-lactone) or pseudo-phosphorylation of α6-tubulin increased its partitioning into MTs as compared to controls, and produced longer, more stable MTs. Following expression of the plus-end binding protein GFP-EB1, DAG-lactone accelerated the formation and increased the number of nascent MTs. Expression of S165D-α6-tubulin promoted Rac1 activation and Rac1-dependent cell motility. These findings call attention to PKC-mediated phosphorylation of α-tubulin as a novel mechanism for controlling the dynamics of MTs that result in cell movement.

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“…Combretastatin A-4 phosphate was found to block blood flow in capillaries supporting cancerous cells by completely disrupting the endothelial cell integrity leading to rapid tumor cell death [ 14 , 15 ]. These inhibitors lead to microtubule disorganization and renders cell apoptosis [ 16 ]. However, the use of these previously identified tubulin inhibitors were restricted on account of excessive toxicity, drug resistance and scarce bioavailability [ 17 - 20 ].…”

Section: Introductionmentioning

confidence: 99%

Fragment based group QSAR and molecular dynamics mechanistic studies on arylthioindole derivatives targeting the α-β interfacial site of human tubulin

et al. 2014

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BackgroundA number of microtubule disassembly blocking agents and inhibitors of tubulin polymerization have been elements of great interest in anti-cancer therapy, some of them even entering into the clinical trials. One such class of tubulin assembly inhibitors is of arylthioindole derivatives which results in effective microtubule disorganization responsible for cell apoptosis by interacting with the colchicine binding site of the β-unit of tubulin close to the interface with the α unit. We modelled the human tubulin β unit (chain D) protein and performed docking studies to elucidate the detailed binding mode of actions associated with their inhibition. The activity enhancing structural aspects were evaluated using a fragment-based Group QSAR (G-QSAR) model and was validated statistically to determine its robustness. A combinatorial library was generated keeping the arylthioindole moiety as the template and their activities were predicted.ResultsThe G-QSAR model obtained was statistically significant with r2 value of 0.85, cross validated correlation coefficient q2 value of 0.71 and pred_r2 (r2 value for test set) value of 0.89. A high F test value of 65.76 suggests robustness of the model. Screening of the combinatorial library on the basis of predicted activity values yielded two compounds HPI (predicted pIC50 = 6.042) and MSI (predicted pIC50 = 6.001) whose interactions with the D chain of modelled human tubulin protein were evaluated in detail. A toxicity evaluation resulted in MSI being less toxic in comparison to HPI.ConclusionsThe study provides an insight into the crucial structural requirements and the necessary chemical substitutions required for the arylthioindole moiety to exhibit enhanced inhibitory activity against human tubulin. The two reported compounds HPI and MSI showed promising anti cancer activities and thus can be considered as potent leads against cancer. The toxicity evaluation of these compounds suggests that MSI is a promising therapeutic candidate. This study provided another stepping stone in the direction of evaluating tubulin inhibition and microtubule disassembly degeneration as viable targets for development of novel therapeutics against cancer.

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Microtubules as a Target in Cancer Therapy

Cited by 4 publications

References 99 publications

Antimitotic drugs in the treatment of cancer

Antimitotic drugs in the treatment of cancer

Phosphorylation of α‐tubulin by protein kinase C stimulates microtubule dynamics in human breast cells

Fragment based group QSAR and molecular dynamics mechanistic studies on arylthioindole derivatives targeting the α-β interfacial site of human tubulin

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