Cepharanthine activates caspases and induces apoptosis in Jurkat and K562 human leukemia cell lines

Wu, Jianghong; Suzuki, Haruhiko; Zhou, Yi; Liu, Wei; Yoshihara, Masaharu; Kato, Masashi; Akhand, Anwarul A.; Hayakawa, Akihiro; Takeuchi, Keigo; Hossain, Khaled; Kurosawa, Mio; Nakashima, Izumi

doi:10.1002/jcb.1155

Cited by 56 publications

(47 citation statements)

References 68 publications

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“…Second, CEP might indirectly inhibit tumor growth by enhancing the immunological responses of the host [29,30] . Third, CEP could induce tumor cell apoptosis by interfering with vital signaling pathways such as the nuclear factor kappa B (NF-κB) and JNK1/2 signaling pathways [8][9][10] . Because CEP is primarily an anti-inflammation agent, the mechanisms underlying its antitumor activity are closely related to the inhibition of inflammatory signaling [3] .…”

Section: Discussionmentioning

confidence: 99%

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Inhibition of the STAT3 signaling pathway is involved in the antitumor activity of cepharanthine in SaOS2 cells

et al. 2012

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Section: Discussionmentioning

confidence: 99%

“…The pharmacological activities of CEP include the reversal of multidrug resistance [5][6][7] , antitumor activity [8][9][10] and inhibiting the production of inflammatory mediators [11][12][13][14] .…”

Section: Introductionmentioning

confidence: 99%

Inhibition of the STAT3 signaling pathway is involved in the antitumor activity of cepharanthine in SaOS2 cells

et al. 2012

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“…30) Ceparanthine at 5-10 µM caused remarkable degradation of the Bcr-Abl protein and induced apoptosis in K562 cells. 31) Inhibition of tyrosine kinase activity of Bcr-Abl by STI571 also induced apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Reversal of the resistance to STI571 in human chronic myelogenous leukemia K562 cells

Mukai

Fang²,

Furukawa³

et al. 2003

Cancer Science

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STI571, an Abl-specific tyrosine kinase inhibitor, selectively kills Bcr-Abl-containing cells in vitro and in vivo. However, some chronic myelogenous leukemia (CML) cell lines are resistant to STI571. We evaluated whether STI571 interacts with P-glycoprotein (P-gp) and multidrug resistance protein 1 (MRP1), and examined the effect of agents that reverse multidrug resistance (MDR) on the resistance to SI571 in MDR cells. STI571 inhibited the [ 125 I]azidoagosterol A-photolabeling of P-gp, but not that of MRP1. K562/MDR cells that overexpress P-gp were 3.67 times more resistant to STI571 than the parental Philadelphia-chromosome-positive (Ph + + + +) CML K562 cells, and this resistance was most effectively reversed by cepharanthine among the tested reversing agents. The concentration of STI571 required to completely inhibit tyrosine phosphorylation in K562/MDR cells was about 3 times higher than that in K562 cells, and cepharanthine abolished the difference. In KB-G2 cells that overexpress P-gp, but not BcrAbl, 2.5 µ µ µ µM STI571 partly reversed the resistance to vincristine (VCR), paclitaxel, etoposide (VP-16) and actinomycin D (ACD) but not to Adriamycin (ADM) or colchicine. STI571 increased the accumulation of VCR, but not that of ADM in KB-G2 cells. STI571 did not reverse resistance to any agent in KB/MRP cells that overexpress MRP1. These findings suggest that STI571 is a substrate for P-gp, but is less efficiently transported by P-gp than VCR, and STI571 is not a substrate for MRP1. Among the tested reversing agents that interact with P-gp, cepharanthine was the most effective agent for the reversal of the resistance to STI571 in K562/ MDR cells. Furthermore, STI571 itself was a potent reversing agent for MDR in P-gp-expressing KB-G2 cells. (Cancer Sci 2003; 94: 557-563)

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“…CEP has been reported to exert antitumor effects in numerous cancers by inhibiting cancer cell proliferation (11), cell cycle progression (12), tumor invasion (13), generating reactive oxygen species (ROS) (11,14), inducing cell apoptosis (11,14,15), regulating cell survival signaling pathways (16,17) and increasing the competence of the host (18,19). It was also identified to potentiate the anticancer effects of other chemotherapeutic agents (20)(21)(22), and was able to circumvent the multidrug resistance of doxorubicin, vincristine and other anticancer agents (21,(23)(24)(25)(26).…”

Section: Introductionmentioning

confidence: 99%

Cepharanthine exerts antitumor activity on choroidal melanoma by reactive oxygen species production and c-Jun N-terminal kinase activation

et al. 2017

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Abstract. Choroidal melanoma is the most common primary intraocular tumor in adults. Cepharanthine (CEP), a natural alkaloid extracted from the roots of Stephania cepharantha Hayata, has been demonstrated to inhibit the proliferation of various cancer cells. However, its potential anticancer effect in choroidal melanoma has not been clarified yet. In the present study, it was identified that CEP may potently inhibit the proliferation of human choroidal melanoma cells, induce cell death and cell cycle arrest, and activate cellular apoptotic proteins, including Bcl-2-associated X protein, caspase and poly(ADP-ribose) polymerase. Results also revealed that CEP induced the cellular production of reactive oxygen species (ROS) and led to cytochrome c release, whereas concurrent treatment with N-acetyl-L-cysteine (a ROS scavenger) attenuated the situation. In addition, CEP was also revealed to activate c-Jun N-terminal kinase (JNK) 1 and 2, whereas inhibition of JNK1/2 partially abrogated the proliferation inhibitory effect of CEP, indicating that JNK1 and JNK2 were involved in CEP-triggered cellular apoptosis. In addition, the anticancer effects of CEP were also observed in a choroidal melanoma xenograft model. In summary, the results of the present study demonstrated that CEP is effective in suppressing human choroidal melanoma cell and tumor cell proliferation, and that CEP may therefore represent a potentially novel therapeutic agent for the treatment of choroidal melanoma. IntroductionChoroidal melanoma is the most common primary intraocular tumor in adults (1,2). The mean incidence of choroidal melanoma in the USA is ~6 novel cases/10 6 people every year (3). Currently, there are several treatment protocols for primary choroidal melanoma, including surgery, radiation therapy, thermotherapy and external beam proton therapy (4-7). The 5-year relative survival rate of choroidal melanoma is ~80% when the tumors are confined to the eyes (3,8). However, patients with choroidal melanoma have a high risk of developing metastasis (typically to the liver), which is usually fatal with a median survival time of 6-9 months subsequent to the detection of liver metastasis (3,8). Therefore, development of novel effective therapies for choroidal melanoma is required urgently.Cepharanthine(CEP; 6',12'-dimethoxy-2,2'-dimethyl-6,7-[methylenebis(oxy)]oxyacanthan) is a biscoclaurine alkaloid extracted from the roots of the plant Stephania cepharantha Hayata, which has been broadly used in Japan for chemoprevention and treatment of numerous diseases by virtue of its anti-inflammatory and immunomodulatory activities (9,10). CEP has been reported to exert antitumor effects in numerous cancers by inhibiting cancer cell proliferation (11), cell cycle progression (12), tumor invasion (13), generating reactive oxygen species (ROS) (11,14), inducing cell apoptosis (11,14,15), regulating cell survival signaling pathways (16,17) and increasing the competence of the host (18,19). It was also identified to potentiate the anticancer effects of oth...

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Cepharanthine activates caspases and induces apoptosis in Jurkat and K562 human leukemia cell lines

Cited by 56 publications

References 68 publications

Inhibition of the STAT3 signaling pathway is involved in the antitumor activity of cepharanthine in SaOS2 cells

Inhibition of the STAT3 signaling pathway is involved in the antitumor activity of cepharanthine in SaOS2 cells

Reversal of the resistance to STI571 in human chronic myelogenous leukemia K562 cells

Cepharanthine exerts antitumor activity on choroidal melanoma by reactive oxygen species production and c-Jun N-terminal kinase activation

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