A novel anti-microtubule agent with carbazole and benzohydrazide structures suppresses tumor cell growth in vivo

Ohira, Makoto; Iwasaki, Yuka W.; Tanaka, Chika; Kuroki, M; Matsuo, Naoki; Kitamura, Takayoshi; Yukuhiro, Masaki; Morimoto, Hiroyuki; Pang, Nisha; Liu, Bei; Kiyono, Tohru; Amemiya, Masahide; Tanaka, Kozo; Yoshida, Kazumasa; Sugimoto, Nozomi; Ohshima, Takashi; Fujita, Masatoshi

doi:10.1016/j.bbagen.2015.04.013

Cited by 9 publications

(27 citation statements)

References 33 publications

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“…described 2 analogs based on a different scaffold (NP-10 and NP-14) that arrested cells in mitosis with abnormal mitotic spindles, yet, only the most potent compound, NP-14, inhibited tubulin polymerization in a cell-free assay. 52 The authors observed some differences in the number of centrosomes in cells treated with the 2 analogs, however, the molecular target(s) of NP-10 remains unknown. 52 …”

Section: Discussionmentioning

confidence: 99%

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Discovery of thalicthuberine as a novel antimitotic agent from nature that disrupts microtubule dynamics and induces apoptosis in prostate cancer cells

et al. 2018

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We report for the first time the mechanism of action of the natural product thalicthuberine (TH) in prostate and cervical cancer cells. TH induced a strong accumulation of LNCaP cells in mitosis, severe mitotic spindle defects, and asymmetric cell divisions, ultimately leading to mitotic catastrophe accompanied by cell death through apoptosis. However, unlike microtubule-binding drugs (vinblastine and paclitaxel), TH did not directly inhibit tubulin polymerization when tested in a cell-free system, whereas it reduced cellular microtubule polymer mass in LNCaP cells. This suggests that TH indirectly targets microtubule dynamics through inhibition of a critical regulator or tubulin-associated protein. Furthermore, TH is not a major substrate for P-glycoprotein (Pgp), which is responsible for multidrug resistance in numerous cancers, providing a rationale to further study TH in cancers with Pgp-mediated treatment resistance. The identification of TH's molecular target in future studies will be of great value to the development of TH as potential treatment of multidrug-resistant tumors.

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Section: Discussionmentioning

confidence: 99%

“… 52 The authors observed some differences in the number of centrosomes in cells treated with the 2 analogs, however, the molecular target(s) of NP-10 remains unknown. 52 …”

Section: Discussionmentioning

confidence: 99%

Discovery of thalicthuberine as a novel antimitotic agent from nature that disrupts microtubule dynamics and induces apoptosis in prostate cancer cells

et al. 2018

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“…However, NP-10 does not suppress the tubulin polymerization, and microtubule formation is only partially inhibited in NP-10-treated cells 5 . In addition, NP-10 does not affect the kinase activity of Aurora B, Plk1, and Cdk1, or the ATPase activity of the CENP-E, Eg5, and KIFC1 kinesins 5 . The mechanism(s) underlying the cancer cell-selective inhibition of mitotic progression by NP-10 remains unclear.…”

Section: Introductionmentioning

confidence: 87%

“…We previously reported the identification of novel antimitotic agents with carbazole and benzohydrazide structures including N ′-[(9-ethyl-9 H -carbazol-3-yl)methylene]-2-iodobenzohydrazide (code number NP-10), N ′-[(9-ethyl-9 H -carbazol-3-yl)methylene]-4-iodobenzohydrazide (code number NP-14), and N ′-[(9-ethyl-9 H -carbazol-3-yl)methylene]-2-methylbenzohydrazide (code number HND-007). Among them, NP-14 and HND-007 inhibit tubulin polymerization in vitro , suggesting that mitotic arrest in cells treated with these compounds is partly due to such inhibitory activity against tubulin polymerization 5 . However, NP-10 does not suppress the tubulin polymerization, and microtubule formation is only partially inhibited in NP-10-treated cells 5 .…”

Section: Introductionmentioning

confidence: 99%

“…Among them, NP-14 and HND-007 inhibit tubulin polymerization in vitro , suggesting that mitotic arrest in cells treated with these compounds is partly due to such inhibitory activity against tubulin polymerization 5 . However, NP-10 does not suppress the tubulin polymerization, and microtubule formation is only partially inhibited in NP-10-treated cells 5 . In addition, NP-10 does not affect the kinase activity of Aurora B, Plk1, and Cdk1, or the ATPase activity of the CENP-E, Eg5, and KIFC1 kinesins 5 .…”

Section: Introductionmentioning

confidence: 99%

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Identification of candidate molecular targets of the novel antineoplastic antimitotic NP-10

Yokoyama

Yukuhiro

Iwasaki

et al. 2019

Sci Rep

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We previously reported the identification of a novel antimitotic agent with carbazole and benzohydrazide structures: N′-[(9-ethyl-9H-carbazol-3-yl)methylene]-2-iodobenzohydrazide (code number NP-10). However, the mechanism(s) underlying the cancer cell-selective inhibition of mitotic progression by NP-10 remains unclear. Here, we identified NP-10-interacting proteins by affinity purification from HeLa cell lysates using NP-10-immobilized beads followed by mass spectrometry. The results showed that several mitosis-associated factors specifically bind to active NP-10, but not to an inactive NP-10 derivative. Among them, NUP155 and importin β may be involved in NP-10-mediated mitotic arrest. Because NP-10 did not show antitumor activity in vivo in a previous study, we synthesized 19 NP-10 derivatives to identify more effective NP-10-related compounds. HMI83-2, an NP-10-related compound with a Cl moiety, inhibited HCT116 cell tumor formation in nude mice without significant loss of body weight, suggesting that HMI83-2 is a promising lead compound for the development of novel antimitotic agents.

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NMK-BH2, a novel microtubule-depolymerising bis (indolyl)-hydrazide-hydrazone, induces apoptotic and autophagic cell death in cervical cancer cells by binding to tubulin at colchicine – site

Mukherjee

Kumar

Tantak

et al. 2020

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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A novel anti-microtubule agent with carbazole and benzohydrazide structures suppresses tumor cell growth in vivo

Cited by 9 publications

References 33 publications

Discovery of thalicthuberine as a novel antimitotic agent from nature that disrupts microtubule dynamics and induces apoptosis in prostate cancer cells

Discovery of thalicthuberine as a novel antimitotic agent from nature that disrupts microtubule dynamics and induces apoptosis in prostate cancer cells

Identification of candidate molecular targets of the novel antineoplastic antimitotic NP-10

NMK-BH2, a novel microtubule-depolymerising bis (indolyl)-hydrazide-hydrazone, induces apoptotic and autophagic cell death in cervical cancer cells by binding to tubulin at colchicine – site

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