Ketoconazole-Induced Apoptosis through P53-Dependent Pathway in Human Colorectal and Hepatocellular Carcinoma Cell Lines

Ho, Yuan Soon; Tsai, Pei Wen; Yu, Cheng; Liu, Hsu Ling; Chen, Rong Jane; Lin, Ju‐Li

doi:10.1006/taap.1998.8467

Cited by 33 publications

(38 citation statements)

References 41 publications

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“…6 In agreement with the PARP fragmentation results shown in Figure 2, lower right, indicating greater activity in cells treated with RuCl 2 (KTZ) 2 , we also found increased caspase activation in C8161 melanoma exposed to this complex, using an antibody that recognizes only activated caspase-3 (Fig. 3, upper).…”

Section: Preferential Caspase-3 Activation By Rucl 2 (Ktz) 2 In C8161supporting

confidence: 90%

“…33 Thus, we investigated the potential antitumor activity of stable Ru(II) complexes that do not need to be reduced but are related to NAMI in that they contain imidazole-type ligands such as KTZ and CTZ, which have themselves displayed some activity in their uncomplexed form. [1][2][3][4][5][6][7][8] Our report shows that the antitumor efficacy of KTZ or CTZ is preferentially evident in their complexes with Ru(II). In contrast, compounds without an azole-Ru(II) interaction, like RuCl 2 (MeCN) 4 , were essentially as inactive as the DMSO vehicle solvent (Fig.…”

Section: Discussionmentioning

confidence: 65%

“…In other experiments, we also used mut p53 melanoma WM164 cells (kindly provided by Dr. M. Herlyn, Wistar Institute, Philadelphia, PA), HT-29 colon carcinoma 6 or A431 epidermoid carcinoma 21 (ATCC, Rockville, MD).…”

Section: Cellsmentioning

confidence: 99%

“…This observation was of interest since HT-29 carcinoma, known to harbor mut p53, shows poor response to KTZ compared to wt p53 carcinoma cells. 6 …”

Section: Preferential Caspase-3 Activation By Rucl 2 (Ktz) 2 In C8161mentioning

confidence: 99%

“…4 This finding was preceded by a report that KTZ exerts a cytostatic effect on human prostate cancer cell lines resistant to microtubule-active drugs, like vinblastine and paclitaxel, and enhances the response to these drugs. 5 Among the mechanisms involved in its anticarcinoma action, it has been reported that KTZ induces apoptosis through a p53-dependent pathway 6 and induces G 0 /G 1 arrest 7 in colorectal and hepatocellular carcinoma lines. Another azole derivative which shows potentially useful antitumor activity is CTZ, recognized as a calmodulin antagonist and inhibitor of glycolysis and known to be the primary energy source in most cancer cells.…”

mentioning

confidence: 99%

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Tumor apoptosis induced by ruthenium(II)‐ketoconazole is enhanced in nonsusceptible carcinoma by monoclonal antibody to EGF receptor

Anzellotti

Sánchez‐Delgado

Rieber

2004

Intl Journal of Cancer

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KTZ, originally developed as an antifungal agent, exhibits concentration-dependent inhibitory and potentiating effects on microtubule drugs like vinblastine at concentration ranges near plasma levels of KTZ attained in human subjects. 1 KTZ is a cytochrome P-450 inhibitor that inhibits adrenal steroidogenesis 2 and shows antiglucocorticoid activity. 3 KTZ synergizes with docetaxel in the treatment of hormone-dependent cancer. 4 This finding was preceded by a report that KTZ exerts a cytostatic effect on human prostate cancer cell lines resistant to microtubule-active drugs, like vinblastine and paclitaxel, and enhances the response to these drugs. 5 Among the mechanisms involved in its anticarcinoma action, it has been reported that KTZ induces apoptosis through a p53-dependent pathway 6 and induces G 0 /G 1 arrest 7 in colorectal and hepatocellular carcinoma lines. Another azole derivative which shows potentially useful antitumor activity is CTZ, recognized as a calmodulin antagonist and inhibitor of glycolysis and known to be the primary energy source in most cancer cells. 8 CTZ induced significant reduction in glycolysis and ATP levels, which led to tumor cell destruction after 3 hr. 8 There is a need to enhance the efficacy of potentially useful anticancer agents like KTZ and CTZ and to develop new compounds capable of activity against tumor cells refractory to apoptosis since the latter property usually correlates with drug resistance.Since genetic alterations involving p53 mutation frequently correlate with decreased response to cancer chemotherapy, 9,10 we investigated whether Ru(II) complexes with CTZ or KTZ 11-13 are more effective than the parent compounds at promoting cell death in tumors with such genetic changes. The reason for this study with Ru(II)-azole complexes is to expand the range of potentially useful antitumor Ru agents since an Ru(III) complex like NAMI-A, 14 -16 which may require reduction of its Ru(III) moiety to act, has shown promising anticancer activity in initial clinical trials. 15 The effects of NAMI-A are often compared to the widely known anticancer drug cisplatin, similarly based on another transition metal. 17 Interestingly, most of the Ru complexes tested to date, including NAMI-A, have not been strikingly more cytotoxic than cisplatin, the most appropriate reference control. 17 While the effect of NAMI-A on metastasis inhibition was previously described in several models, 14,15 its mechanism of action was demonstrated only recently. In vitro studies showed that 100 M NAMI-A, active on lung tumor metastases, 14 induced apoptosis of a transformed ECV304 human endothelial cell line by promoting caspase-3 activation 16 and release of mitochondrial cytochrome c, 16,18 hallmarks of cellular suicide. The mitochondrial damage induced by NAMI-A 16 is compatible with the effect of 20 -50 M CTZ, which induces glycolysis-related hexokinase detachment from mitochondria and loss of viability in B16 melanoma. 8 Since apoptosis induced by 50 M KTZ is decreased in colorectal and hepatocellu...

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Section: Preferential Caspase-3 Activation By Rucl 2 (Ktz) 2 In C8161supporting

confidence: 90%

Section: Discussionmentioning

confidence: 65%

Section: Cellsmentioning

confidence: 99%

“…This observation was of interest since HT-29 carcinoma, known to harbor mut p53, shows poor response to KTZ compared to wt p53 carcinoma cells. 6 …”

Section: Preferential Caspase-3 Activation By Rucl 2 (Ktz) 2 In C8161mentioning

confidence: 99%

mentioning

confidence: 99%

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Tumor apoptosis induced by ruthenium(II)‐ketoconazole is enhanced in nonsusceptible carcinoma by monoclonal antibody to EGF receptor

Anzellotti

Sánchez‐Delgado

Rieber

2004

Intl Journal of Cancer

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Griseofulvin potentiates antitumorigenesis effects of nocodazole through induction of apoptosis and G2/M cell cycle arrest in human colorectal cancer cells

Duh

Jeng

et al. 2000

Intl Journal of Cancer

139

116

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In vitro and in vivo studies of the anticancer action of terbinafine in human cancer cell lines: G0/G1 p53‐associated cell cycle arrest

Lee

Chen

Tseng

et al. 2003

Intl Journal of Cancer

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The current options for treating human cancer are limited to excision surgery, general chemotherapy, radiation therapy and, in a minority of breast cancers that rely on estrogen for their growth, antiestrogen therapy. Although there has been considerable improvement in the treatment of cancer, the overall prognosis remains not good. Therefore, investigators continue to search for new therapeutic strategies. One approach, as pursued in our study, seeks to identify medicinal agents capable of retarding the cell cycle and/or activating the cellular apoptotic response in the cancerous cells.Recently, we have shown that a number of antifungal agents exert antiproliferative and/or apoptotic activities in various malignant cells in vitro and in vivo. For instance, our previous studies showed that ketoconazole (Nizoral) induced cell cycle arrest at the G0/G1 phase of the cell cycle and the occurrence of apoptosis in hepatoma and colon cancer cells, 1,2 whereas griseofulvin (Grifulvin) induced apoptosis and cell cycle arrest at the G2/M phase through abnormal microtubule polymerization. 3 We also showed that combined treatment of griseofulvin and nocodazole (ND) significantly enhanced the therapeutic efficacy in the treatment of cancerous cells in athymic mice bearing COLO 205 tumor xenografts. 3 In the present study, we examined the antitumoral activity of terbinafine (TB) (Lamisil).TB is a newly synthesized oral antimycotic drug in the allylamines class: a fungicidal agent that inhibits ergosterol synthesis at the stage of squalene epoxidation. 4 It shows a good safety profile and relatively few drug interactions. 5 The cream form and oral tablet of TB have been approved for clinical uses in the United States. 6 The oral formulation has been on the market in various countries for more than 8 years, and as of 1997, more than 7.5 million individuals had been treated with this drug. 7 Here, we showed that TB inhibited the proliferation of tumor cells in vitro and in vivo. The experimental findings reported below highlight the molecular mechanisms of TB-induced antitumoral activity. MATERIAL AND METHODS Cell lines and cell cultureThe HT 29 (p53 mutant) 8 and COLO 205 (p53 wild) 9 cell lines were isolated from human colon adenocarcinoma (American Type

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Ketoconazole-Induced Apoptosis through P53-Dependent Pathway in Human Colorectal and Hepatocellular Carcinoma Cell Lines

Cited by 33 publications

References 41 publications

Tumor apoptosis induced by ruthenium(II)‐ketoconazole is enhanced in nonsusceptible carcinoma by monoclonal antibody to EGF receptor

Tumor apoptosis induced by ruthenium(II)‐ketoconazole is enhanced in nonsusceptible carcinoma by monoclonal antibody to EGF receptor

Griseofulvin potentiates antitumorigenesis effects of nocodazole through induction of apoptosis and G2/M cell cycle arrest in human colorectal cancer cells

In vitro and in vivo studies of the anticancer action of terbinafine in human cancer cell lines: G0/G1 p53‐associated cell cycle arrest

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