Salvinal, a Novel Microtubule Inhibitor Isolated from <i>Salvia miltiorrhizae</i> Bunge (Danshen), with Antimitotic Activity in Multidrug-Sensitive and -Resistant Human Tumor Cells

Chang, Jang Yang; Chang, Chin-Chih; Kuo, Ching Chuan; Chen, Li Tzong; Wein, Yung Shung; Kuo, Yueh Hsiung

doi:10.1124/mol.65.1.77

Cited by 89 publications

(54 citation statements)

References 31 publications

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“…As previously reported, 6-hour paclitaxel treatment significantly increased polymerized tubulin in EBC-1 cells. In contrast, vincristine treatment decreased assembled microtubules (31). As expected, tivantinib treatment inhibited tubulin polymerization in a concentration-dependent manner similar to that by vincristine treatment but surprisingly did not inhibit c-MET and its downstream AKT and ERK signaling pathways.…”

Section: Tivantinib Inhibited Tubulin Polymerization In Cellssupporting

confidence: 69%

Tivantinib (ARQ 197) Exhibits Antitumor Activity by Directly Interacting with Tubulin and Overcomes ABC Transporter–Mediated Drug Resistance

Aoyama

Katayama

Oh‐hara

et al. 2014

Molecular Cancer Therapeutics

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Tivantinib (ARQ197) was first reported as a highly selective inhibitor of c-MET and is currently being investigated in a phase III clinical trial. However, as recently reported by us and another group, tivantinib showed cytotoxic activity independent of cellular c-MET status and also disrupted microtubule dynamics. To investigate if tivantinib exerts its cytotoxic activity by disrupting microtubules, we quantified polymerized tubulin in cells and xenograft tumors after tivantinib treatment. Consistent with our previous report, tivantinib reduced tubulin polymerization in cells and in mouse xenograft tumors in vivo. To determine if tivantinib directly binds to tubulin, we performed an in vitro competition assay. Tivantinib competitively inhibited colchicine but not vincristine or vinblastine binding to purified tubulin. These results imply that tivantinib directly binds to the colchicine binding site of tubulin. To predict the binding mode of tivantinib with tubulin, we performed computer simulation of the docking pose of tivantinib with tubulin using GOLD docking program. Computer simulation predicts tivantinib fitted into the colchicine binding pocket of tubulin without steric hindrance. Furthermore, tivantinib showed similar IC 50 values against parental and multidrug-resistant cells. In contrast, other microtubule-targeting drugs, such as vincristine, paclitaxel, and colchicine, could not suppress the growth of cells overexpressing ABC transporters. Moreover, the expression level of ABC transporters did not correlate with the apoptosis-inducing ability of tivantinib different from other microtubule inhibitor. These results suggest that tivantinib can overcome ABC transporter-mediated multidrug-resistant tumor cells and is potentially useful against various tumors. Mol Cancer Ther; 13(12); 2978-90. Ó2014 AACR.

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Section: Tivantinib Inhibited Tubulin Polymerization In Cellssupporting

confidence: 69%

Tivantinib (ARQ 197) Exhibits Antitumor Activity by Directly Interacting with Tubulin and Overcomes ABC Transporter–Mediated Drug Resistance

Aoyama

Katayama

Oh‐hara

et al. 2014

Molecular Cancer Therapeutics

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“…Previous reports indicated that several chemicals regulated the Cdc2/cyclinB complex and arrest cell cycle in G2-M phase through Cdc25C and Myt-1 proteins. The elevated hyperphosphorylation of Cdc25C and declined unphosphorylated Cdc25C (interphase Cdc25C) in human cancer cells were parallel with the activation of Cdc2/cyclinB after exposure of chemicals Chang et al, 2004;Kuo et al, 2004;Singh et al, 2004]. Griseofulvin, an anti-fungal agent caused the down-regulation of Myt-1 protein expression, contributed the abnormal G2-M cell cycle arrest [Ho et al, 2001].…”

Section: Discussionmentioning

confidence: 96%

Anti‐proliferative effects of evodiamine on human prostate cancer cell lines DU145 and PC3

Kan¹,

Yu²,

Pu³

et al. 2007

J of Cellular Biochemistry

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Prostate carcinoma is one of the most common malignant tumors and has become a more common cancer in men. Previous studies demonstrated that evodiamine (EVO) exhibited anti-tumor activities on several cancers, but its effects on androgen-independent prostate cancer are unclear. In the present study, the action mechanisms of EVO on the growth of androgen-independent prostate cancer cells (DU145 and PC3 cells) were explored. EVO dramatically inhibited the growth and elevated cytotoxicity of DU145 and PC3 cells. The flow cytometric analysis of EVO-treated cells indicated a block of G2/M phase and an elevated level of DNA fragmentation. The G2/M arrest was accompanied by elevated Cdc2 kinase activity, an increase in expression of cyclin B1 and phosphorylated Cdc2 (Thr 161), and a decrease in expression of phosphorylated Cdc2 (Tyr 15), Myt-1, and interphase Cdc25C. TUNEL examination showed that EVO-induced apoptosis was observed at 72 h. EVO elevated the activities of caspase 3, 8, and 9 in DU145 cells, while in PC3 cells only the activities of caspase 3 and 9 were elevated. EVO also triggered the processing of caspase 3 and 9 in both DU145 and PC3 cells. We demonstrate that roscovitine treatment result in the reversion of G2/M arrest in response to EVO in both DU145 and PC3. However, inhibitory effect of roscovitine on EVO-induced apoptosis could only be observed in DU145 rather than PC3. In DU145, G2/M arrest might be a signal for initiation of EVO-triggered apoptosis. Whereas EVO-triggered PC3 apoptosis might be independent of G2/M arrest. These results suggested that EVO inhibited the growth of prostate cancer cell lines, DU145 and PC3, through an accumulation at G2/M phase and an induction of apoptosis.

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“…Multidrug resistance and DNA repair are of prime concern with DNA alkylating agents. 7,8 Intriguingly, BO-1090 was more effective in Taxol-and vincristine-resistant KB cell lines (Supporting Information Table 4), which exhibit the pg170/ MDR1 resistance phenotype, 14 than in parental KB cells. The resistance ratio (ratio of IC50 of resistant to parental cell) of BO-1090 was 0.93 for Taxol-resistant and 0.731 for vincristine-resistant cells, indicating that BO-1090 may bypass the MDR1 effect.…”

Section: Cancer Therapymentioning

confidence: 98%

The novel DNA alkylating agent BO‐1090 suppresses the growth of human oral cavity cancer in xenografted and orthotopic mouse models

Sanjiv

Suman

et al. 2011

Intl Journal of Cancer

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Oral cancer is the fourth-most common cause of death in males and overall the sixth-most common cause of cancer death in Taiwan. Surgery, radiotherapy and chemotherapy combined with other therapies are the most common treatments for oral cavity cancer. Although cisplatin, 5-fluorouracil and docetaxel are commonly used clinically, there is no drug specific for oral cavity cancer. Here, we demonstrated that derivatives of 3a-aza-cyclopenta[a]indene, a class of newly synthesized alkylating agents, may be drugs more specific for oral cancer based on its potent in vitro cytotoxicity to oral cancer cells and on in vivo xenografts. Among them, BO-1090, bis(hydroxymethyl)-3a-aza-cyclopenta[a]indene derivative, targeted DNA for its cytotoxic effects as shown by inhibition of DNA synthesis (bromodeoxyuridine-based DNA synthesis assay), induction of DNA crosslinking (alkaline gel shift assay), and induction of DNA single-stranded breaks (Comet assay) and double-stranded breaks (c-H2AX focus formation). Following DNA damage, BO-1090 induced G1/S-phase arrest and apoptosis in oral cancer cell lines. The therapeutic potential of BO-1090 was tested in mice that received a xenograft of oral cavity cancer cell lines (SAS or Cal 27 cells). Intravenous injection of BO-1090 significantly suppressed tumor growth in comparison to control mice. BO-1090 also significantly reduced the tumor burden in orthotopic mouse models using SAS cells. There was no significant adverse effect of BO-1090 treatment with this dosage based on whole blood count, biochemical enzyme profiles in plasma and histopathology of various organs in mouse. Taken together, our current results demonstrate that B0-1090 may have potential as a treatment for oral cavity cancer.Oral cavity cancer involving the lesions occurred in the tongue, oropharynx and floor of the mouth is a prevalent type of cancer in developing countries such as India, Pakistan, Bangladesh and Taiwan. 1 In south-central Asia, it is the third-most common cancer, with an average incidence rate of 1 to 10 per 100,000 people. The incidence of oral cancer is also increasing in developed countries. 2 The treatments of oral cancer include surgery, radiation or chemotherapy, depending on the stage and nature of the tumor. 3,4 Unfortunately, only marginal improvement is seen in many patients, and a complete cure is often not achieved. Half of the patients diagnosed with oral cancer succumb to death within 5 years, and for those who survive, the quality of life remains poor. 1 Thus, development of a drug specific for oral cavity cancer is needed so that substantial improvement in treatment can be achieved.The cytotoxic and antitumor properties of alkylating agents are due to their ability to covalently bind to DNA. There are two types of DNA alkylating agents, monofunctional and bifunctional agents. Monofunctional alkylating agents mainly damage DNA by forming methylated adducts, whereas the damage induced by bifunctional alkylating agents includes monoadducts, intrastrand crosslinks and interstrand crossli...

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Salvinal, a Novel Microtubule Inhibitor Isolated from Salvia miltiorrhizae Bunge (Danshen), with Antimitotic Activity in Multidrug-Sensitive and -Resistant Human Tumor Cells

Cited by 89 publications

References 31 publications

Tivantinib (ARQ 197) Exhibits Antitumor Activity by Directly Interacting with Tubulin and Overcomes ABC Transporter–Mediated Drug Resistance

Tivantinib (ARQ 197) Exhibits Antitumor Activity by Directly Interacting with Tubulin and Overcomes ABC Transporter–Mediated Drug Resistance

Anti‐proliferative effects of evodiamine on human prostate cancer cell lines DU145 and PC3

The novel DNA alkylating agent BO‐1090 suppresses the growth of human oral cavity cancer in xenografted and orthotopic mouse models

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