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Why a Combination of WP 631 and Epo B is an Improvement on the Drugs Singly - Involvement in the Cell Cycle and Mitotic Slippage
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 Title & Authors
Why a Combination of WP 631 and Epo B is an Improvement on the Drugs Singly - Involvement in the Cell Cycle and Mitotic Slippage
Bukowska, Barbara; Rogalska, Aneta; Forma, Ewa; Brys, Magdalena; Marczak, Agnieszka;
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Our previous studies clearly demonstrated that a combination of WP 631 and Epo B has higher activity against ovarian cancer cells than either of these compounds used separately. In order to fully understand the exact mechanism of action in combination, we assessed effects on the cell cycle of SKOV-3 cells. We evaluated three control points essential for WP 631 and Epo B action to determine which cell cycle-regulating proteins (CDK1/cyclin B complex, EpCAM or HMGB1) mediate activity. The effects of the drug on the cell cycle were measured based on the nuclear DNA content using flow cytometry. Expression of cell cycle-regulating genes was analyzed using real-time PCR. It was discovered that WP 631, at the tested concentration, did not affect the SKOV-3 cell cycle. Epo B caused significant G2/M arrest, whereas the drug combination induced stronger apoptosis and lower mitotic arrest than Epo B alone. This is very important information from the point of view of the fight against cancer, as, while mitotic arrest in Epo B-treated cells could be overcame after DNA damage repair, apoptosis which occurs after mitotic slippage in combination-treated cells is irreversible. It clearly explains the higher activity of the drug combination in comparison to Epo B alone. Epo B acts via the CDK1/cyclin B complex and has the ability to inhibit CDK1, which may be a promising strategy for ovarian cancer treatment in the future. The drug combination diminishes EpCAM and HMGB1 expression to a greater degree than either WP 631 and Epo B alone. Owing to the fact that the high expression of these two proteins is a poor prognostic factor for ovarian cancer, a decrease in their expression, observed in our studies, may result in improved efficacy of cancer therapy. The presented findings show that the combination of WP 631 and Epo B is a better therapeutic option than either of these drugs alone.
Apoptosis;cell cycle;epothilone B;ovarian cancer;WP 631;
 Cited by
Arikan SK, Kasap B, Yetimalar H, et al (2014). Impact of prognostic factors on survival rates in patients with ovarian carcinoma. Asian Pac J Cancer Prev, 15, 6087-94. crossref(new window)

Asraf H, Avunie-Masala R, Hershfinkel M, et al (2015). Mitotic slippage and expression of survivin are linked to differential sensitivity of human cancer cell-lines to the Kinesin-5 inhibitor monastrol. PLoS One, 10, 129255.

Blagosklonny MV (2007). Mitotic arrest and cell fate: why and how mitotic inhibition of transcription drives mutually exclusive events. Cell Cycle, 6, 70-4. crossref(new window)

Brito DA, Rieder CL (2006). Mitotic checkpoint slippage in humans occurs via cyclin B destruction in the presence of an active checkpoint. Curr Biol, 16, 1194-200. crossref(new window)

Buzgariu W, Crescenzi M, Galliot B (2014). Robust G2 pausing of adult stem cells in Hydra. Differentiation, 87, 83-99. crossref(new window)

Chaves-Perez A, Mack B, Maetzel D, et al (2013). EpCAM regulates cell cycle progression via control of cyclin D1 expression. Oncogene, 32, 641-50. crossref(new window)

Chen J, Liu X, Zhang J, et al (2012). Targeting HMGB1 inhibits ovarian cancer growth and metastasis by lentivirus-mediated RNA interference. J Cell Physiol, 227, 3629-38. crossref(new window)

Chen JG, Yang CP, Cammer M, et al (2003). Gene expression and mitotic exit induced by microtubule-stabilizing drugs. Cancer Res, 63, 7891-9.

Chen S, Chen X, Xiu YL, et al (2015a). MicroRNA-490-3P targets CDK1 and inhibits ovarian epithelial carcinoma tumorigenesis and progression. Cancer Lett, 362, 122-30. crossref(new window)

Chen XX, Xie FF, Zhu XJ, et al (2015b). Cyclin-dependent kinase inhibitor dinaciclib potently synergizes with cisplatin in preclinical models of ovarian cancer. Oncotarget, 6, 14926-39. crossref(new window)

Chen Y, Liu ZJ, Liu J, et al (2014). Inhibition of metastasis and invasion of ovarian cancer cells by crude polysaccharides from rosa roxburghii tratt in vitro. Asian Pac J Cancer Prev, 15, 10351-4.

Chow JP, Poon RY, Ma HT (2011). Inhibitory phosphorylation of cyclin-dependent kinase 1 as a compensatory mechanism for mitosis exit. Mol Cell Biol, 31, 1478-91. crossref(new window)

Chuang P-Y, Huang C, Huang H-C (2013). The use of a combination of tamoxifen and doxorubicin synergistically to induce cell cycle arrest in BT483 cells by down-regulating CDK1, CDK2 and cyclin D expression. J Pharmaceutical Technol Drug Res, 2, 12. crossref(new window)

Cui C, Wang Y, Wang Y, et al (2013). Alsterpaullone, a Cyclin-Dependent Kinase Inhibitor, Mediated Toxicity in HeLa Cells through Apoptosis-Inducing Effect. J Anal Methods Chem, 2013, 602091.

Endo K, Mizuguchi M, Harata A, et al (2010). Nocodazole induces mitotic cell death with apoptotic-like features in Saccharomyces cerevisiae. FEBS Lett, 584, 2387-92. crossref(new window)

Enserink JM, Kolodner RD (2010). An overview of Cdk1-controlled targets and processes. Cell Div, 5, 11. crossref(new window)

Gong H, Zuliani P, Komuravelli A, et al (2010). Analysis and verification of the HMGB1 signaling pathway. BMC Bioinformatics, 11, 10. crossref(new window)

Griffin D, Wittmann S, Guo F, et al (2003). Molecular determinants of epothilone B derivative (BMS 247550) and Apo-2L/TRAIL-induced apoptosis of human ovarian cancer cells. Gynecol Oncol, 89, 37-47. crossref(new window)

Jiao Y, Wang HC, Fan SJ (2007). Growth suppression and radiosensitivity increase by HMGB1 in breast cancer. Acta Pharmacol Sin, 28, 1957-67. crossref(new window)

Kobayashi H, Saito T, Sato K, et al (2014). Phosphorylation of cyclin-dependent kinase 5 (Cdk5) at Tyr-15 is inhibited by Cdk5 activators and does not contribute to the activation of Cdk5. J Biol Chem, 289, 19627-36. crossref(new window)

Lee SH, Son SM, Son DJ, et al (2007). Epothilones induce human colon cancer SW620 cell apoptosis via the tubulin polymerization independent activation of the nuclear factor-kappaB/IkappaB kinase signal pathway. Mol Cancer Ther, 6, 2786-97. crossref(new window)

Li H, Huang W, Luo R (2015). The microRNA-325 inhibits hepatocellular carcinoma progression by targeting high mobility group box 1. Diagn Pathol, 10, 117. crossref(new window)

Lin CW, Liao MY, Lin WW, et al (2012). Epithelial cell adhesion molecule regulates tumor initiation and tumorigenesis via activating reprogramming factors and epithelial-mesenchymal transition gene expression in colon cancer. J Biol Chem, 287, 39449-59. crossref(new window)

Lupertz R, Watjen W, Kahl R, et al (2010). Dose- and time-dependent effects of doxorubicin on cytotoxicity, cell cycle and apoptotic cell death in human colon cancer cells. Toxicol, 271, 115-21. crossref(new window)

Mansilla S, Priebe W, Portugal J (2006). Mitotic catastrophe results in cell death by caspase-dependent and caspase-independent mechanisms. Cell Cycle, 5, 53-60. crossref(new window)

Marczak A, Bukowska B, Rogalska A (2014). WP 631 and Epo B synergize in SKOV-3 human ovarian cancer cells. Environ Toxicol Pharmacol, 37, 256-66. crossref(new window)

McClendon AK, Dean JL, Rivadeneira DB, et al (2012). CDK4/6 inhibition antagonizes the cytotoxic response to anthracycline therapy. Cell Cycle, 11, 2747-55. crossref(new window)

Mu Y, Sa N, Yu L, et al (2014). Epithelial cell adhesion molecule is overexpressed in hypopharyngeal carcinoma and suppresses the metastasis and proliferation of the disease when downregulated. Oncol Lett, 8, 175-82. crossref(new window)

Mukhtar E, Adhami VM, Mukhtar H (2014). Targeting microtubules by natural agents for cancer therapy. Mol Cancer Ther, 13, 275-84. crossref(new window)

Munz M, Kieu C, Mack B, et al (2004). The carcinoma-associated antigen EpCAM upregulates c-myc and induces cell proliferation. Oncogene, 23, 5748-58. crossref(new window)

Nakayama S, Torikoshi Y, Takahashi T, et al (2009). Prediction of paclitaxel sensitivity by CDK1 and CDK2 activity in human breast cancer cells. Breast Cancer Res, 11, 12.

Nunna S, Reinhardt R, Ragozin S, et al (2014). Targeted methylation of the epithelial cell adhesion molecule (EpCAM) promoter to silence its expression in ovarian cancer cells. PLoS One, 9, 87703. crossref(new window)

Ohmori H, Yi L, Fujii K, Sasaki T, Kuniyasu H (2015). High mobility group box 1 induces cancer aggressiveness and drug resistance. Ann Clin Pathol, 3, 1042.

Orth JD, Loewer A, Lahav G, et al (2012). Prolonged mitotic arrest triggers partial activation of apoptosis, resulting in DNA damage and p53 induction. Mol Biol Cell, 23, 567-76. crossref(new window)

Pellicciotta I, Yang CP, Venditti CA, et al (2013). Response to microtubule-interacting agents in primary epithelial ovarian cancer cells. Cancer Cell Int, 13, 33. crossref(new window)

Pozarowski P, Huang X, Gong RW, et al (2004). Simple, semiautomatic assay of cytostatic and cytotoxic effects of antitumor drugs by laser scanning cytometry: effects of the bis-intercalator WP631 on growth and cell cycle of T-24 cells. Cytometry A, 57, 113-9.

Riffell JL, Janicke RU, Roberge M (2011). Caspase-3-dependent mitotic checkpoint inactivation by the small-molecule inducers of mitotic slippage SU6656 and geraldol. Mol Cancer Ther, 10, 839-49. crossref(new window)

Risinger AL, Mooberry SL (2011). Cellular studies reveal mechanistic differences between taccalonolide A and paclitaxel. Cell Cycle, 10, 2162-71. crossref(new window)

Rogalska A, Bukowska B, Marczak A (2014). Caspases and ROS - dependent mechanism of action mediated by combination of WP 631 and epothilone B. Anticancer Agents Med Chem, 14, 1261-70. crossref(new window)

Saito T, Chiba T, Yuki K, et al (2013). Metformin, a diabetes drug, eliminates tumor-initiating hepatocellular carcinoma cells. PLoS One, 8, 70010. crossref(new window)

Schnell U, Cirulli V, Giepmans BN (2013). EpCAM: structure and function in health and disease. Biochim Biophys Acta, 1828, 1989-2001. crossref(new window)

Senese S, Lo YC, Huang D, et al (2014). Chemical dissection of the cell cycle: probes for cell biology and anti-cancer drug development. Cell Death Dis, 5, 1462. crossref(new window)

Shahabi S, Yang CP, Goldberg GL, et al (2010). Epothilone B enhances surface EpCAM expression in ovarian cancer Hey cells. Gynecol Oncol, 119, 345-50. crossref(new window)

Soysal SD, Muenst S, Barbie T, et al (2013). EpCAM expression varies significantly and is differentially associated with prognosis in the luminal B HER2(+), basal-like, and HER2 intrinsic subtypes of breast cancer. Br J Cancer, 108, 1480-7. crossref(new window)

Tang HL, Tang HM, Mak KH, et al (2012). Cell survival, DNA damage, and oncogenic transformation after a transient and reversible apoptotic response. Mol Biol Cell, 23, 2240-52. crossref(new window)

Tse BW, Collins A, Oehler MK, et al (2014). Antibody-based immunotherapy for ovarian cancer: where are we at? Ann Oncol, 25, 322-31. crossref(new window)

Tsoyi K, Jang HJ, Nizamutdinova IT, et al (2011). Metformin inhibits HMGB1 release in LPS-treated RAW 264.7 cells and increases survival rate of endotoxaemic mice. Br J Pharmacol, 162, 1498-508. crossref(new window)

van der Gun BT, Melchers LJ, Ruiters MH, et al (2010). EpCAM in carcinogenesis: the good, the bad or the ugly. Carcinogenesis, 31, 1913-21. crossref(new window)

Villamarin S, Mansilla S, Ferrer-Miralles N, et al (2003). A comparative analysis of the time-dependent antiproliferative effects of daunorubicin and WP631. Eur J Biochem, 270, 764-70. crossref(new window)

Yang JS, Hour MJ, Huang WW, et al (2010). MJ-29 inhibits tubulin polymerization, induces mitotic arrest, and triggers apoptosis via cyclin-dependent kinase 1-mediated Bcl-2 phosphorylation in human leukemia U937 cells. J Pharmacol Exp Ther, 334, 477-88. crossref(new window)

Ye H, Karim AA, Loh XJ (2014). Current treatment options and drug delivery systems as potential therapeutic agents for ovarian cancer: a review. Mater Sci Eng C Mater Biol Appl, 45, 609-19. crossref(new window)

Zhang T, Hu X, Cai Y, et al (2014). Metformin protects against hyperglycemia-induced cardiomyocytes injury by inhibiting the expressions of receptor for advanced glycation end products and high mobility group box 1 protein. Mol Biol Rep, 41, 1335-40. crossref(new window)