Vinblastine

Vinblastine is a cytotoxic alkaloid used against various cancer types. Vinblastine inhibits the formation of microtubule and suppresses nAChR with an IC50 of 8.9 μM.

In Vitro:Vinblastine does not depolymerize spindle microtubules, yet it powerfully blocks mitosis (for example, IC50 0.8 nM in HeLa cells) and cells die by apoptosis[2]. In NB4 cells, vinblastine produces alteration of p53 and DNA fragmentation. Vinblastine treatment has an antiproliferative effect via the induction of apoptosis producing Bax/Bcl-2 imbalance. Vinblastine treatment suppresses NFκB expression and depresses NFκB-DNA binding activity while maintaining JNK activation that subsequently results in apoptotic response through caspase-dependent pathway[3]. Vinblastine is found to trigger apoptosis as evidenced by the loss of mitochondrial membrane potential, the release of both cytochrome c and apoptosis inducing factor, activation of caspase-9 and 3, and cleavage of Poly (ADP-ribose)-Polymerase[4].

In Vivo:Vinblastine is a widely used anticancer drug with undesired side effects. Its conjugation with carrier molecules could be an efficient strategy to reduce these side effects[5].

References:
[1]. McKay DB, et al. Nicotinic and nonnicotinic receptor-mediated actions of vinblastine. Proc Soc Exp Biol Med. 1993 Jul;203(3):372-6. [2]. Pandya P, et al. Molecular recognition pattern of cytotoxic alkaloid vinblastine with multiple targets. J Mol Graph Model. 2014 Nov;54:1-9. [3]. Calviño E, et al. JNK and NFκB dependence of apoptosis induced by vinblastine in human acute promyelocytic leukaemia cells. Cell Biochem Funct. 2015 Jun;33(4):211-9. [4]. Selimovic D, et al. Vinblastine-induced apoptosis of melanoma cells is mediated by Ras homologous A protein (Rho A) via mitochondrial and non-mitochondrial-dependent mechanisms. Apoptosis. 2013 Aug;18(8):980-97. [5]. Bánóczi Z, et al. Synthesis and in vitro antitumor effect of vinblastine derivative-oligoarginine conjugates. Bioconjug Chem. 2010 Nov 17;21(11):1948-55.

Autonomic neuropathy resulting in recurrent laryngeal nerve palsy in an HIV patient with Hodgkin lymphoma receiving vinblastine and antiretroviral therapy.[Pubmed:24828552]

Int J STD AIDS. 2015 Mar;26(3):206-8.

Hoarseness of voice due to vocal cord paresis as a result of recurrent laryngeal nerve palsy has been well recognised. Recurrent laryngeal nerve palsy is commonly caused by compression due to tumour or lymph nodes or by surgical damage. Vinca alkaloids are well known to cause peripheral neuropathy. However, vinca alkaloids causing recurrent laryngeal nerve palsy has been reported rarely in children. We report a case of an adult patient with HIV who developed hoarseness of voice due to vocal cord paralysis during Vinblastine treatment for Hodgkin lymphoma. Mediastinal and hilar lymph node enlargement in such patients may distract clinicians from considering alternative causes of recurrent laryngeal nerve palsy, with potential ensuing severe or even life-threatening stridor.

Leishmania amazonensis: Increase in ecto-ATPase activity and parasite burden of vinblastine-resistant protozoa.[Pubmed:25176449]

Exp Parasitol. 2014 Nov;146:25-33.

Leishmania amazonensis is a protozoan parasite that induces mucocutaneous and diffuse cutaneous lesions upon infection. An important component in treatment failure is the emergence of drug-resistant parasites. It is necessary to clarify the mechanism of resistance that occurs in these parasites to develop effective drugs for leishmaniasis treatment. Promastigote forms of L. amazonensis were selected by gradually increasing concentrations of Vinblastine and were maintained under continuous drug pressure (resistant cells). Vinblastine-resistant L. amazonensis proliferated similarly to control parasites. However, resistant cells showed changes in the cell shape, irregular flagella and a decrease in rhodamine 123 accumulation, which are factors associated with the development of resistance, suggesting the MDR phenotype. The Mg-dependent-ecto-ATPase, an enzyme located on cell surface of Leishmania parasites, is involved in the acquisition of purine and participates in the adhesion and infectivity process. We compared control and resistant L. amazonensis ecto-enzymatic activities. The control and resistant Leishmania ecto-ATPase activities were 16.0 +/- 1.5 nmol Pi x h(-1) x 10(-7) cells and 40.0 +/- 4.4 nmol Pi x h(-1) x 10(-7)cells, respectively. Interestingly, the activity of other ecto-enzymes present on the L. amazonensis cell surface, the ecto-5' and 3'-nucleotidases and ecto-phosphatase, did not increase. The level of ecto-ATPase modulation is related to the degree of resistance of the cell. Cells resistant to 10 muM and 60 muM of Vinblastine have ecto-ATPase activities of 22.7 +/- 0.4 nmol Pi x h(-1) x 10(-7) cells and 33.8 +/- 0.8 nmol Pi x h(-1) x 10(-7)cells, respectively. In vivo experiments showed that both lesion size and parasite burden in mice infected with resistant parasites are greater than those of L. amazonensis control cells. Furthermore, our data established a relationship between the increase in ecto-ATPase activity and greater infectivity and severity of the disease caused by Vinblastine-resistant L. amazonensis promastigotes. Taken together, these data suggest that ecto-enzymes could be potential therapeutic targets in the struggle against the spread of leishmaniasis, a neglected world-wide public health problem.

Vinblastine rapidly induces NOXA and acutely sensitizes primary chronic lymphocytic leukemia cells to ABT-737.[Pubmed:23723123]

Mol Cancer Ther. 2013 Aug;12(8):1504-14.

Proteins of the BCL2 family provide a survival mechanism in many human malignancies, including chronic lymphocytic leukemia (CLL). The BCL2 inhibitor ABT-263 (navitoclax) is active in clinical trials for lymphoid malignancies, yet resistance is expected on the basis of preclinical models. We recently showed that Vinblastine can dramatically sensitize several leukemia cell lines to ABT-737 (the experimental congener of ABT-263). The goal of these experiments was to determine the impact of Vinblastine on ABT-737 sensitivity in CLL cells isolated from peripheral blood and to define the underlying mechanism. Freshly isolated CLL cells from 35 patients, as well as normal lymphocytes and platelets, were incubated with various microtubule-disrupting agents plus ABT-737 to assess sensitivity to the single agents and the combination. ABT-737 and Vinblastine displayed a range of sensitivity as single agents, and Vinblastine markedly sensitized all CLL samples to ABT-737 within six hours. Vinblastine potently induced the proapoptotic protein PMAIP1 (NOXA) in both time- and dose-dependent manner and this was required for the observed apoptosis. Combretastatin A4, which dissociates microtubules by binding to a different site, had the same effect, confirming that interaction of these agents with microtubules is the initial target. Similarly, vincristine and vinorelbine induced NOXA and enhanced CLL sensitivity to ABT-737. Furthermore, Vinblastine plus ABT-737 overcame stroma-mediated resistance to ABT-737 alone. Apoptosis was induced with clinically achievable concentrations with no additional toxicity to normal lymphocytes or platelets. These results suggest that vinca alkaloids may improve the clinical efficacy of ABT-263 in patients with CLL.

Vinblastine-induced apoptosis of melanoma cells is mediated by Ras homologous A protein (Rho A) via mitochondrial and non-mitochondrial-dependent mechanisms.[Pubmed:23564313]

Apoptosis. 2013 Aug;18(8):980-97.

Despite the availability of melanoma treatment at the primary site, the recurrence of local melanoma can metastasize to any distant organ. Currently, the available therapies for the treatment of metastatic melanoma are of limited benefit. Thus, the functional analysis of conventional therapies may help to improve their efficiency in the treatment of metastatic melanoma. In the present study, the exposure of melanoma cells to Vinblastine was found to trigger apoptosis as evidenced by the loss of mitochondrial membrane potential, the release of both cytochrome c and apoptosis inducing factor, activation of caspase-9 and 3, and cleavage of Poly (ADP-ribose)-Polymerase. Also, Vinblastine enhances the phosphorylation of Ras homologous protein A, the accumulation of reactive oxygen species, the release of intracellular Ca(2+), as well as the activation of apoptosis signal-regulating kinase 1, c-jun-N-terminal kinase, p38, inhibitor of kappaBalpha (IkappaBalpha) kinase, and inositol requiring enzyme 1alpha. In addition, Vinblastine induces the DNA-binding activities of the transcription factor NF-kappaB, HSF1, AP-1, and ATF-2, together with the expression of HSP70 and Bax proteins. Moreover, inhibitory experiments addressed a central role for Rho A in the regulation of Vinblastine-induced apoptosis of melanoma cells via mitochondrial and non-mitochondrial-dependent mechanisms. In conclusion, the present study addresses for the first time a central role for Rho A in the modulation of Vinblastine-induced apoptosis of melanoma cells and thereby provides an insight into the molecular action of Vinblastine in melanoma treatment.

[Antifungal azoles exacerbate vinblastine-related hyponatremia in ALL children].[Pubmed:25338594]

Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2014 Oct;22(5):1386-90.

The purpose of this study was to investigate the clinical characteristics and the treatments of patients with Vinblastine-related hyponatremia which was aggravated by azole antifungal agents in children with acute lymphoblastic leukemia(ALL). A total of 93 children treated with Vinblastine in our department during April 2013 to March 2014 were enrolled in this study and were divided into 3 groups:VDLD, VDLD with azoles antifungal, VDLD with non azoles antifungal. The incidence and severity of hyponatremia were statistically analysed. The results showed that (1) the incidence of hyponatremia in VDLD group was 93.1%(67/72),100%(13/13) in VDLD with azoles antifungal group, and 75%(6/8) in VDLD with non-azoles antifungal, there was no statistically difference between these three groups. (2) Incidence of moderate to severe hyponatremia (Na<129 mmol/L) in VDLD with azoles antifungal group was(9/13,69.2%),which was significartly higher than those in VDLD group (22/72, 30.6%) and in VDLD with non azoles antifungal group (1/8, 12.5%). However, the difference between VDLD group and VDLD with non azoles antifungal group were not statistical significant. (3) the lowest serum sodium level in VDLD with azoles antifungal group (124.0 +/- 8.6 mmol/L) was significantly lower than that in VDLD group (130.8 +/- 3.8 mmol/L)and VDLD+non azoles antifungal group(132.9 +/- 4.9 mmol/L). Otherwise, the difference was not statistically significant between VDLD group and VDLD with non azoles antifungal group. (4) four children with severe hyponatremia showed convulsions and coma which all belong to VDLD with azoles antifungal group. The children with hyponatremia were restricted intake of fluid, adjusted the liquid tension, supplied hypertonic sodium and given diuretic, the serum sodium value gradually picked up in these children. In 4-11 months' follow-up, no hyponatremia happened again in these children. It is concluded that the incident of hyponatremia in children treated with Vinblastine is high, but most of them seldom showed clinical characteristics. The combination of antifungal azoles with Vinblastine can increase the incidence and severity of hyponatremia. Therefore, combined administration of azole antifungals with Vinblastine should be avoided.