p53-Mediated Cell Cycle Arrest and Apoptosis Induced by Shikonin via a Caspase-9-Dependent Mechanism in Human Malignant Melanoma A375-S2 Cells

Wu, Zhiyong; Li-jun, WU; Lin-hao, LI; Tashiro, Shin‐ichi; Onodera, Satoshi; Ikejima, Takashi

doi:10.1254/jphs.94.166

Cited by 108 publications

(95 citation statements)

References 31 publications

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“…Shikonin, isolated from roots of the medicinal herb Lithosper mum er ythrorhizon Siebold Zucc [14] , is a Chinese herbal medicine with various biological activities, including anti-microbial, anti-fungal, anti-HIV, anti-inflammatory, anti-tumor, and wound-healing activities [15][16][17] . However, its toxicity has limited it as a therapeutic agent [14,17] .…”

Section: Discussionmentioning

confidence: 99%

“…Generally, tumorigenesis and tumor progression are strongly associated with abnormal apoptosis. It has been shown that shikonin and its derivatives induce apoptosis of tumor cells [16,19,20] . Our data demonstrate that acetylshikonin could also induce apoptosis of SGC-7901 cells with typical apoptotic alterations, including morphological changes and positive TUNEL assay, DNA fragmentation and apoptotic Apoptosis is a complex process regulated by a variety of factors [21,22] .…”

Section: Discussionmentioning

confidence: 99%

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Inhibitory effect of acetylshikonin on human gastric carcinoma cell line SGC-7901 in vitro and in vivo

Zeng¹,

Liu²,

Zhou³

2009

WJG

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AIM:To investigate the inhibitory effect of acetylshikonin on human gastric carcinoma cell line SGC-7901 and its mechanism. METHODS:MTT assay was used to assess the inhibitory effect of acetylshikonin on proliferation o f S G C-7 9 0 1 c e l l s . A p o p t o s i s -i n d u c i n g e f f e c t was determined by flow cytometry and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling with Hoechst staining. Expression of mRNA and protein in Bcl-2 and Bax was analyzed by reverse transcription-polymerase chain reaction and Western blot. Antitumor effect of acetylshikonin on a mouse SGC-7901 model was also determined. RESULTS:

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Inhibitory effect of acetylshikonin on human gastric carcinoma cell line SGC-7901 in vitro and in vivo

Zeng¹,

Liu²,

Zhou³

2009

WJG

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“…36 It is well established that the central role of p53 is partly associated with the regulation of cell apoptosis via Caspase-3, Caspase-9, Bcl-2 and Bax. [37][38][39] However, apoptosis with specific regard to Bcl-2 or caspase is also triggered by p53 independent manner, such as Par-4 or p21 WAF1/CIP1 pathway. [40][41][42] Cyclin B1 overexpression is usually caused by the inactive function of p53.…”

Section: Discussionmentioning

confidence: 99%

Loss of Cyclin B1 followed by downregulation of Cyclin A/Cdk2, apoptosis and antiproliferation in Hela cell line

Xie¹,

An²,

Kang³

et al. 2005

Intl Journal of Cancer

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Recent studies have shown that Cyclin B1 is overexpressed in various tumor types but present at low levels in normal tissues. To explore the possibility of employing Cyclin B1 as an anticancer target, we knocked down Cyclin B1 in an HeLa cell line using RNA interference (RNAi). Subsequently, we monitored cell cyclerelated molecules by Western blot together with immunofluorescence and determined cell cycle distribution by flow cytometry. XTT and soft agar colony growth experiments were performed to detect cell viability and proliferation. Furthermore, we analyzed cell apoptosis by measuring Bcl-2 and Bax protein level and DNAladder assay. After performing Cyclin B1 RNAi, Cyclin B1, Cyclin A and Cdk2 protein levels were found to be markedly downregulated, whereas Cdc2 was almost unaffected; S-phase fraction increased significantly; HeLa cell viability and cell colony forming ability were markedly diminished after the RNAi; Bcl-2 was noticeably attenuated but Bax was hardly changed; and HeLa cells displayed typical DNA ladder. The loss of Cyclin B1 resulted in the downregulation of Cyclin A and Cdk2, S-phase delay and eventually led to cell apoptosis and the decrease of cell viability and proliferation. Our studies suggest that Cyclin B1 may be a promising anticancer target. ' 2005 Wiley-Liss, Inc.Key words: Cyclin B1; RNA interference (RNAi); Cyclin A; Cyclindependent kinase 2 (Cdk2); apoptosis; HeLaThe prevalent methods employed to treat advanced cervical cancer are chemotherapy, radiation therapy or concomitant chemoradiotherapy, which have exerted immense effect on survival. However, chemotherapy may evoke cytotoxic and sensitization effects, some of which are life threatening. 1 Many attempts have been made to apply to advanced cervical cancer, such as developing therapeutic vaccination against human papillomavirus (HPV) antigens, 2 gene therapy using tissue-specific promoters, 3 adenovirus-mediated p53 delivery 4 and recombinant interleukin-12 adenovirus plus E7 protein.5 Nonetheless, few of them have been satisfying, and thus, it is urgent to explore novel therapy to maximize specificity and minimize off-target effect.Cyclin B1 is the regulatory subunit of Cdk1 serine/threonine kinase, and the accumulation of Cyclin B1 is a prerequisite for mitotic initiation in the late G2 phase in mammalian cells. [6][7][8] Because Cyclin B1 has a direct effect on mitosis, the overexpression of Cyclin B1 may lead to uncontrolled cell proliferation, neoplastic transformation and tumorigenesis.9-11 Hence, Cyclin B1 may be an oncogene in cancer.12 Recent studies have shown that Cyclin B1 is overexpressed in breast cancer, nonsmall cell lung cancer, colorectal cancer, prostate cancer and squamous cell carcinoma of the head and neck but not in normal cells, indicating that it can be a specific anticancer target. [12][13][14][15][16][17] Other studies indicate that tumors overexpressing Cyclin B1 may be resistant to radiotherapy and that Cyclin B1 may be an indicator for the risk of locoregional recurrence and metastasis in hea...

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“…Studies suggest that the anticancer activities of shikonin derivatives may be attributed to their ability to down-regulate anti-apoptotic Bcl-2 family members, such as Bcl-2 and Bcl-xL, generate reactive oxygen species (ROS), activate caspases [11,12], inhibit EGFR phosphorylation [13] and arrest the cell cycle through p53 upregulation [14]. However, the precise mechanisms employed by shikonin to repress cancer growth remain to be defined.…”

Section: Introductionmentioning

confidence: 99%

Induction of apoptosis by shikonin through a ROS/JNK-mediated process in Bcr/Abl-positive chronic myelogenous leukemia (CML) cells

2008

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This study examined the signaling events induced by shikonin that lead to the induction of apoptosis in Bcr/ Abl-positive chronic myelogenous leukemia (CML) cells (e.g., K562, LAMA84). Treatment of K562 cells with shikonin (e.g., 0.5 μM) resulted in profound induction of apoptosis accompanied by rapid generation of reactive oxygen species (ROS), striking activation of c-Jun-N-terminal kinase (JNK) and p38, marked release of the mitochondrial proteins cytochrome c and Smac/DIABLO, activation of caspase-9 and -3, and cleavage of PARP. Scavenging of ROS completely blocked all of the above-mentioned events (i.e., JNK and p38 phosphorylation, cytochrome c and Smac/DIABLO release, caspase and PARP cleavage, as well as the induction of apoptosis) following shikonin treatment. Inhibition of JNK and knock-down of JNK1 significantly attenuated cytochrome c release, caspase cleavage and apoptosis, but did not affect shikonin-mediated ROS production. Additionally, inhibition of caspase activation completely blocked shikonin-induced apoptosis, but did not appreciably modify shikonin-mediated cytochrome c release or ROS generation. Altogether, these findings demonstrate that shikonin-induced oxidative injury operates at a proximal point in apoptotic signaling cascades, and subsequently activates the stress-related JNK pathway, triggers mitochondrial dysfunction, cytochrome c release, and caspase activation, and leads to apoptosis. Our data also suggest that shikonin may be a promising agent for the treatment of CML, as a generator of ROS.

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p53-Mediated Cell Cycle Arrest and Apoptosis Induced by Shikonin via a Caspase-9-Dependent Mechanism in Human Malignant Melanoma A375-S2 Cells

Cited by 108 publications

References 31 publications

Inhibitory effect of acetylshikonin on human gastric carcinoma cell line SGC-7901 in vitro and in vivo

Inhibitory effect of acetylshikonin on human gastric carcinoma cell line SGC-7901 in vitro and in vivo

Loss of Cyclin B1 followed by downregulation of Cyclin A/Cdk2, apoptosis and antiproliferation in Hela cell line

Induction of apoptosis by shikonin through a ROS/JNK-mediated process in Bcr/Abl-positive chronic myelogenous leukemia (CML) cells

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