The Biological Activity of the Novel Vinca Alkaloids 4-chlorochablastine and 4-chlorochacristine

Author(s): Gracia Montag, Helga Stopper, Quoc Anh Ngo, Henning Hintzsche*.

Journal Name: Current Cancer Drug Targets

Volume 19 , Issue 3 , 2019

  Journal Home
Translate in Chinese
Become EABM
Become Reviewer

Abstract:

Background: Vinca alkaloids are important cancer drugs belonging to the class of antimitotic agents. The most commonly used substances are vinblastine and vincristine, other compounds are vinorelbine and vinflunine. All of them are very effective drugs but their use is limited by severe side-effects including neurotoxicity and bone marrow depression. Therefore, it is very important to develop novel vinca alkaloids with similar efficacy but lower toxicity.

Methods: Here, we analyzed two new compounds, 4-chlorochablastine and 4-chlorochacristine, with regard to their biological activity. These novel compounds were applied to a leukemia cell line at clinically relevant concentrations. For comparison, the established vinca alkaloids vinblastine, vincristine, vinorelbine, and vinflunine were also tested.

Results: Both novel substances decreased cellular proliferation. Apoptosis was found to be increased using two different methods reflecting early and late apoptosis. Cell cycle analysis revealed a clear decrease in G1-cells and an increase in G2/M-cells indicating an arrest in mitosis. In general, 4- chlorochablastine and 4-chlorochacristine caused these effects at concentrations higher than those needed for vinblastine, vincristine, and vinorelbine, but the potency was approximately in the range of vinflunine.

Conclusion: Taken together, the results show first indications that these novel vinca alkaloids might be effective and that they warrant further analysis.

Keywords: Cytotoxicity, HL-60 cells, vinca alkaloids, chlorochablastine, chlorochacristine, vinblastine, vincristine, vinflunine, vinorelbine.

[1]
Moudi M, Go R, Yien CY, Nazre M. Vinca alkaloids. Int J Prev Med 2013; 4(11): 1231-5.
[2]
Noble RL, Beer CT, Cutts JH. Role of chance observations in chemotherapy: Vinca rosea. Ann N Y Acad Sci 1958; 76(3): 882-94.
[3]
Lee JC, Harrison D, Timasheff SN. Interaction of vinblastine with calf brain microtubule protein. J Boil Chem 1975; 250(24): 9276-82.
[4]
Gigant B, Wang C, Ravelli RB, et al. Structural basis for the regulation of tubulin by vinblastine. Nature 2005; 435(7041): 519-22.
[5]
Cragg GM. Anticancer Agents from Natural Products. 2nd ed. Boca Raton: CRC Press 2012; p. 767.
[6]
Caron JM, Herwood M. Vinblastine, a chemotherapeutic drug, inhibits palmitoylation of tubulin in human leukemic lymphocytes. Chemotherapy 2007; 53(1): 51-8.
[7]
DeVita VT. DeVita, Hellman, and Rosenberg’s cancer principles & practice of oncology. 2008.
[8]
Binet S, Chaineau E, Fellous A, et al. Immunofluorescence study of the action of navelbine, vincristine and vinblastine on mitotic and axonal microtubules. Int J Cancer 1990; 46(2): 262-6.
[9]
Hill SA, Lonergan SJ, Denekamp J, Chaplin DJ. Vinca alkaloids: anti-vascular effects in a murine tumour. Eur J Cancer 1993; 29A(9): 1320-4.
[10]
Himes RH, Kersey RN, Heller-Bettinger I, Samson FE. Action of the vinca alkaloids vincristine, vinblastine, and desacetyl vinblastine amide on microtubules in vitro. Cancer Res 1976; 36(10): 3798-802.
[11]
Zingirian M, Carbone A. Paracentral and central circular static campimetry on a tangential graph. Ann Ottalmol Clin Ocul 1963; 89: 116-25.
[12]
Scalone S, Sorio R, Bortolussi R, Lombardi D, La Mura N, Veronesi A. Vinorelbine-induced acute reversible peripheral neuropathy in a patient with ovarian carcinoma pretreated with carboplatin and paclitaxel. Acta Oncol 2004; 43(2): 209-11.
[13]
Ngo QA. Nguyen le, A.; Vo, N.B.; Nguyen, T.H.; Roussi, F.; Nguyen, T.H.; Nguyen, V.T. Synthesis and antiproliferativeactivity of new vinca alkaloids containing an alpha,beta-unsaturated aromatic side chain. Bioorg Med Chem Lett 2015; 25(23): 5597-600.
[14]
Collins SJ, Ruscetti FW, Gallagher RE, Gallo RC. Terminal differentiation of human promyelocytic leukemia cells induced by dimethyl sulfoxide and other polar compounds. Proc Natl Acad Sci USA 1978; 75(5): 2458-62.
[15]
Mohamed EY, Sami W, Alotaibi A, Alfarag A, Almutairi A, Alanzi F. Patients’ satisfaction with primary health care centers’ services, Majmaah, Kingdom of Saudi of Saudi Arabia. Int J Health Sci (Qassim) 2015; 9(2): 163-70.
[16]
Gidding CE, Kellie SJ, Kamps WA, de Graaf SS. Vincristine revisited. Crit Rev Oncol Hematol 1999; 29(3): 267-87.
[17]
Detrich HW III, Parker SK, Williams RC Jr, Nogales E, Downing KH. Cold adaptation of microtubule assembly and dynamics. Structural interpretation of primary sequence changes present in the alpha- and beta-tubulins of Antarctic fishes. J Boil Chem 2000; 275(47): 37038-47.
[18]
Ngo QA, Nguyen LA, Vo NB, et al. Synthesis and antiproliferativeactivity of new vinca alkaloids containing an α,β-unsaturated aromatic side chain. Bioorg Med Chem Lett 2015; 25(23): 5597-600.
[19]
Tang DG, Li L, Zhu Z, Joshi B. Apoptosis in the absence of cytochrome c accumulation in the cytosol. Biochem Biophys Res Commun 1998; 242(2): 380-4.
[20]
Landini I, Bartolozzi B, Banchelli I, Degli Innocenti A, Nocentini O, Bernabei PA. In vitro activity of vinorelbine on human leukemia cells. J Chemother 2001; 13(3): 309-15.
[21]
Thomadaki H, Floros KV, Scorilas A. Molecular response of HL-60 cells to mitotic inhibitors vincristine and taxol visualized with apoptosis-related gene expressions, including the new member BCL2L12. Ann N Y Acad Sci 2009; 1171: 276-83.
[22]
Jean-Decoster C, Brichese L, Barret JM, et al. Vinflunine, a new vinca alkaloid: cytotoxicity, cellular accumulation and action on the interphasic and mitotic microtubule cytoskeleton of PtK2 cells. Anticancer Drugs 1999; 10(6): 537-43.
[23]
Bonfil RD, Russo DM, Binda MM, Delgado FM, Vincenti M. Higher antitumor activity of vinflunine than vinorelbine against an orthotopic murine model of transitional cell carcinoma of the bladder. Urol Oncol 2002; 7(4): 159-66.
[24]
Zucker RM, Whittington K, Price BJ. Differentiation of HL-60 cells: cell volume and cell cycle changes. Cytometry 1983; 3(6): 414-8.
[25]
Kolomeichuk SN, Terrano DT, Lyle CS, Sabapathy K, Chambers TC. Distinct signaling pathways of microtubule inhibitors--vinblastine and Taxol induce JNK-dependent cell death but through AP-1-dependent and AP-1-independent mechanisms, respectively. FEBS J 2008; 275(8): 1889-99.


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 19
ISSUE: 3
Year: 2019
Page: [222 - 230]
Pages: 9
DOI: 10.2174/1568009618666180430142233
Price: $58

Article Metrics

PDF: 40
HTML: 3