The Natural Naphthoquinone Plumbagin Exhibits Antiproliferative Activity and Disrupts the Microtubule Network through Tubulin Binding

Acharya, Bipul R.; Bhattacharyya, Bhabatarak; Chakrabarti, Gopal

doi:10.1021/bi800730q

Cited by 71 publications

(79 citation statements)

References 48 publications

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“…6B, where [X] is the concentration of one of the three inhibitors. The dissociation constant (K d ) was determined as described previously (Acharya et al, 2008) using the following equation:…”

Section: Methodsmentioning

confidence: 99%

Novel Betulin Derivatives as Antileishmanial Agents with Mode of Action Targeting Type IB DNA Topoisomerase

Chowdhury

Mukherjee²,

Sengupta³

et al. 2011

Mol Pharmacol

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Toward developing antileishmanial agents with mode of action targeted to DNA topoisomerases of Leishmania donovani, we have synthesized a large number of derivatives of betulin. The compound, a natural triterpene isolated from the cork layer of Betula spp. plants exhibits several pharmacological properties. Three compounds (disuccinyl betulin, diglutaryl dihydrobetulin, and disuccinyl dihydrobetulin) inhibit growth of the parasite as well as relaxation activity of the enzyme type IB topoisomerase [Leishmania donovani topoisomerase I (LdTOP1LS)] of the parasite. Mechanistic studies suggest that these compounds interact with the enzyme in a reversible manner. The stoichiometry of these compounds binding to LdTOP1LS is 1:1 (mole/mole) with a dissociation constant on the order of ϳ10 Ϫ6 M. Unlike CPT, these compounds do not stabilize the cleavage complex; rather, they abrogate the covalent complex formation. In processive mode of relaxation assay condition, these compounds slow down the strand rotation event, which ultimately affects the relaxation of supercoiled DNA. It is noteworthy that these compounds reduce the intracellular parasite burden in macrophages infected with wild-type L. donovani as well as with sodium antimony gluconate resistant parasite (GE1). Taken together, our data suggest that these betulin derivatives can be exploited as potential drug candidates against threatening drug resistant leishmaniasis.

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Section: Methodsmentioning

confidence: 99%

Novel Betulin Derivatives as Antileishmanial Agents with Mode of Action Targeting Type IB DNA Topoisomerase

Chowdhury

Mukherjee²,

Sengupta³

et al. 2011

Mol Pharmacol

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“…Several agents are known to induce cell elongation and to inhibit bacterial cell division by perturbing FtsZ assembly [24][25][26][27][28]. Recently, plumbagin has been shown to bind to tubulin and to inhibit tubulin assembly in vitro [29]. As FtsZ is a prokaryotic homolog of tubulin, and plumbagin caused elongation of bacterial cells, we wished to examine the effect of plumbagin on FtsZ assembly.…”

Section: Introductionmentioning

confidence: 99%

Plumbagin inhibits cytokinesis in Bacillus subtilis by inhibiting FtsZ assembly – a mechanistic study of its antibacterial activity

et al. 2013

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The assembly of FtsZ plays a central role in construction of the cytokinetic Z-ring that orchestrates bacterial cell division. A naturally occurring naphthoquinone, plumbagin, is known to exhibit antibacterial properties against several types of bacteria. In this study, plumbagin was found to perturb formation of the Z-ring in Bacillus subtilis 168 cells and to cause elongation of these cells without an apparent effect on nucleoid segregation, indicating that it may inhibit FtsZ assembly. Furthermore, it bound to purified B. subtilis FtsZ (BsFtsZ) with a dissociation constant of 20.7 AE 5.6 lM, and inhibited the assembly and GTPase activity of BsFtsZ in vitro. Interestingly, plumbagin did not inhibit either the assembly or GTPase activity of Escherichia coli FtsZ (EcFtsZ) in vitro. Using docking analysis, a putative plumbagin-binding site on BsFtsZ was identified, and the analysis indicated that hydrophobic interactions and hydrogen bonds predominate. Based on the in silico analysis, two variants of BsFtsZ, namely D199A and V307R, were constructed to explore the binding interaction of plumbagin and BsFtsZ. The effects of plumbagin on the assembly and GTPase activity of the variant BsFtsZ proteins in vitro indicated that the residues D199 and V307 may be involved in the binding of plumbagin to BsFtsZ. The results suggest that plumbagin inhibits bacterial proliferation by inhibiting the assembly of FtsZ, and provide insight into the binding site of plumbagin on BsFtsZ, which may help in the design of potent FtsZ-targeted antibacterial agents.

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“…Previous studies have demonstrated that PL exhibits anti-Haemonchus contortus (7), anti-bacterial (8), hypolipidaemic and anti-atherosclerotic (9), anti-inflammation (10) and anticancer effects (11,12). The molecular mechanisms of the anticancer effects of PL include inactivition of NF-κB and Bcl-2 (13,14), disruption of the microtubule network (15), breakage of DNA (16), generation of reactive oxygen species (17,18) and cell cycle arrest (19,21). PL was also found to improve the radiation effect in the treatment of mouse tumor xenograft models (22,23).…”

Section: Introductionmentioning

confidence: 99%

Plumbagin induces apoptosis via the p53 pathway and generation of reactive oxygen species in human osteosarcoma cells

et al. 2011

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Abstract. Osteosarcoma, which is the most common primary bone tumor, occurs most frequently in adolescents. A number of studies have indicated that plumbagin (PL) (5-hydroxy-2-methyl-1, 4-naphthoquinone), a compound found in the plants of the Plumbaginaceae and Droseraceae families, possesses anticancer activity. However, its anticancer effects and mechanisms against osteosarcoma have not been explored. To determine the anticancer effect of PL on osteosarcoma cell lines MG-63 and U2OS, cell viability, apoptosis, cell cycle distribution, caspase-3 and caspase-9 activity and intracellular reactive oxygen species (ROS) generation were measured, and Western blot analyses were performed. PL significantly inhibited the growth of osteosarcoma cells, particularly U2OS cells. PL up-regulated the expression of p53 in U2OS cells and p21 in the two osteosarcoma cell lines causing cell cycle arrest by decreasing the expression of murine double minute 2 (MDM2)/ cyclin B1 and cyclin D1. Furthermore, PL altered the ratio of Bax/Bcl-2, and may have triggered the mitochondrial apoptotic pathway, resulting in caspase-3 and caspase-9 activation. We also found that PL induced the generation of ROS in osteosarcoma cell lines. To conclude, PL exerted anticancer activity on osteosarcoma cells by inducing pro-apoptotic signaling and modulating the intracellular ROS that causes induction of apoptosis. These effects may relate to the p53 status.

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The Natural Naphthoquinone Plumbagin Exhibits Antiproliferative Activity and Disrupts the Microtubule Network through Tubulin Binding

Cited by 71 publications

References 48 publications

Novel Betulin Derivatives as Antileishmanial Agents with Mode of Action Targeting Type IB DNA Topoisomerase

Novel Betulin Derivatives as Antileishmanial Agents with Mode of Action Targeting Type IB DNA Topoisomerase

Plumbagin inhibits cytokinesis in Bacillus subtilis by inhibiting FtsZ assembly – a mechanistic study of its antibacterial activity

Plumbagin induces apoptosis via the p53 pathway and generation of reactive oxygen species in human osteosarcoma cells

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