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Abstract

TZT-1027, a newly synthesized dolastatin 10 derivative, is a potent antitumor agent which inhibits microtubule polymerization and perturbs microtubule dynamics. In this report, we investigated whether TZT-1027 inhibited the growth of various human cancer cells, and the cell death caused by TZT-1027 was due to apoptosis. In addition, we elucidated the apoptosis machinery induced by treatment with TZT-1027. The 50% growth-inhibitory concentrations (IC50 values) of TZT-1027 on cancer cells derived from various sources were not more than 5.9 ng/ml. TZT-1027 showed superior cytotoxicity than any other antitumor agents. Next, we evaluated morphological nuclear change, namely, chromatin condensation and DNA fragmentation. We used three cancer cell lines derived from different types in view of having apoptosis related protein, human leukemia HL-60 (in the presence of both Caspase-3 and Bcl-2), human breast cancer MCF-7 (in the absence of Caspase-3), and human prostate cancer DU145 (in the absence of Bcl-2). TZT-1027 induced DNA fragmentation in the presence but not absence of Caspase-3. Nevertheless, apoptic chromatin condensation was observed in all cancer cells even if there was no Caspase-3. Furthermore, we examined whether TZT-1027, microtubule-disrupting agent, influenced cell cycle progression. Flow cytometric analysis revealed the cells treated with TZT-1027, and with the other antimicrotubule agents, to be arrested at the G2/M phase and subsequently to show fragmented DNA smaller than that of G1 phase cells. Moreover, we tested TZT-1027 for its ability to induce Bcl-2 phosphorylation in human cancer cell lines. TZT-1027 and other agents which interacted with microtubules induced Bcl-2 phosphorylation, whereas DNA-damaging agents did not. The present results suggested an association of the growth-inhibitory effect of TZT-1027 with the induction of apoptosis and indicated that the apoptosis induced by TZT-1027 was followed by G2/M arrest even if there was no Caspase-3 or Bcl-2.

Stabilizing versus Destabilizing the Microtubules: A Double-Edge Sword for an Effective Cancer Treatment Option?

“…It shows in vivo antivascular effects in tumoral models overexpressing VEGF and in murine colon tumors, with an increase in vascular permeability, vessel closure, and widespread hemorrhage. Soblidotin also shows antitumoral activity in vincristine-, docetaxel-, and paclitaxel-resistant tumors, which makes it a potential chemotherapy drug for use in tumors which do not respond to other microtubule inhibitors [ 98 ].…”

Advances in Application of Marine Bioactive Peptides in Drug Development

“…并且, Solidotin 可以攻击晚期肿瘤良好的血管系统, 阻止血管 生成, 杀死肿瘤细胞 [41] . Watanabe 等 [42] 发现 Solidotin 的 抗肿瘤活性要优于长春新碱、5-氟尿嘧啶和顺氯氨铂. 在结构上, Solidotin 是用苯乙胺取代 Dolastatin 10 的 Doe 片段而得到的, 它的合成是以与 Dil 片段相关联的化合 物(24)合成 Dov-Val-Dil-Dap-OBzl (32), 三肽 32 进行脱 保护再与苯乙胺(33)反应得到 Solidotin (Scheme 7) [15] .…”

Marine-Derived Angiogenesis Inhibitors for Cancer Therapy

“…Despite these differences, all the 4 inhibitors possess potent cytotoxicity in various tumor cells in vitro and in vivo . They also cause cell cycle arrest in the G 2 /M phase and induce apoptosis [16,17,18,19]. And also due to the differences in their binding to tubulin or their unique structural characteristics, some of them such as plinabulin and laulimalide are highly effective even in cancer cells with resistance to taxol or multidrug resistance (MDR) [14,20].…”