Genistein Sensitizes Bladder Cancer Cells to HCPT Treatment In Vitro and In Vivo via ATM/NF-κB/IKK Pathway-Induced Apoptosis

Wang, Yong; Wang, He; Zhang, Wei; Shao, Chen; Xu, Peng; Shi, Chang Hong; Shi, Jiyuan; Li, Yu Mei; Fu, Qiang; Xue, Wei; Lei, Yong; Gao, Jing; Wang, Juan Ying; Gao, Xiangyang; Li, Jin Qing; Jian, Yuan; Zhang, Yun Tao

doi:10.1371/journal.pone.0050175

Cited by 43 publications

(24 citation statements)

References 30 publications

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“…Flow cytometric analysis revealed that the number of apoptotic cells increased from 20.89% (following treatment with 2.5 nM HCPT) to 97.66% (following treatment with 20 nM HCPT) in a dose-dependent manner. So consistent with earlier observations in other tumor cells [19][20][21][22][23][24], we found that HCPT inhibits the proliferation and viability of SMS-KCNR cells by inducing apoptosis.…”

Section: Discussionsupporting

confidence: 93%

“…Induction of apoptosis in tumor cells is a promising chemopreventive or chemotherapeutic strategy [17,18]. Previous studies have demonstrated that HCPT is able to induce apoptosis in cells of various tumor types, including colon, liver, gastric, prostate and bladder cancer, as well as melanoma [19][20][21][22][23][24]. However, only one study regarding HCPT-induced apoptosis of NB cells has been conducted [25].…”

Section: Discussionmentioning

confidence: 99%

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10-Hydroxycamptothecin induces apoptosis in human neuroblastoma SMS-KCNR cells through p53, cytochrome c and caspase 3 pathways

Zf¹,

Ym²,

Xj³

et al. 2016

neo

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Neuroblastoma (NB), the most common extracranial solid tumor in childhood, remains one of the most challenging types of cancer to treat. Therefore, the search for novel effective drugs for its treatment is essential. The present study used 10-hydroxycamptothecin (HCPT), which is a naturally occurring alkaloid anticancer agent extracted from the Chinese tree, Camptotheca acuminata, and has a strong anticancer activity in vitro and in vivo. HCPT is able to induce apoptosis in cells of various tumor types. However, few studies have been conducted on its efficacy in NB, and its apoptosis-inducing mechanism has not been elucidated. In the present study, the in vitro effects of HCPT on apoptosis in the human NB cell line, SMS-KCNR, and its underlying molecular mechanisms were investigated. Cell proliferation was measured by an MTT assay and apoptosis was measured using DAPI staining and flow cytometric analysis. In addition, western blot analysis was used to evaluate the apoptosis-associated signaling pathways. HCPT was observed to markedly inhibit cell proliferation and induce apoptosis in SMS-KCNR cells at a relatively low concentration (2.5-20 nM). DAPI staining revealed typical apoptotic feature, namely apoptotic body formation. The flow cytometric analysis revealed that the number of apoptotic cells increased from 20.89% (for 2.5 nM) to 97.66% (for 20 nM) following HCPT treatment for 48 h. Western blot analysis revealed that p53, cytoplasmic cytochrome c, cleaved caspase-3 and poly ADP-ribose polymerase (PARP) proteins were significantly upregulated, while the mitochondrial cytochrome c and pro-caspase-3 proteins were downregulated. However, the B-cell lymphoma 2 and Bcl-2-associated X proteins were unaffected. The results indicated that HCPT may inhibit proliferation and induce apoptosis in the SMS-KCNR cells. The possible mechanism of apoptosis induction is the p53-mediated mitochondrial apoptotic signaling pathway, which promotes cytochrome c release and induces apoptosis by activating caspase-3 and PARP. Our study provides experimental evidence for HCPT as a potent therapeutic drug in NB treatment.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

10-Hydroxycamptothecin induces apoptosis in human neuroblastoma SMS-KCNR cells through p53, cytochrome c and caspase 3 pathways

Zf¹,

Ym²,

Xj³

et al. 2016

neo

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“…For example, genistein can induce apoptosis through ATM signaling. 20,21 In T cells etoposide treatment through ATM can also cause apoptosis. 22 ATM signaling can also facilitate liver damage in already damaged fibrotic livers.…”

Section: Discussionmentioning

confidence: 99%

PDE5 inhibitors enhance the lethality of standard of care chemotherapy in pediatric CNS tumor cells

Roberts

Booth

Conley

et al. 2014

Cancer Biology & Therapy

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We determined whether clinically relevant phosphodiesterase 5 (PDE5) inhibitors interacted with clinically relevant chemotherapies to kill medulloblastoma cells. In medulloblastoma cells PDE5 inhibitors interacted in a greater than additive fashion with vincristine/etoposide/cisplatin to cause cell death. Knockdown of PDE5 expression recapitulated the combination effects of PDE5 inhibitor drugs with chemotherapy drugs. Expression of dominant negative caspase 9 did not significantly inhibit chemotherapy lethality but did significantly reduce enhanced killing in combination with the PDE5 inhibitor sildenafil. Overexpression of BCL-XL and c-FLIP-s suppressed individual and combination drug toxicities. Knockdown of CD95 or FADD suppressed drug combination toxicity. Treatment with PDE5 inhibitors and chemotherapy drugs promoted autophagy which was maximal at ~12 h post-treatment, and in a cell type-dependent manner knockdown of Beclin1 or ATG5 either suppressed or enhanced drug combination lethality. PDE5 inhibitors enhanced the induction of chemotherapy-induced DNA damage in a nitric oxide synthase-dependent fashion. In conclusion, our data demonstrate that the combination of PDE5 inhibitors with standard of care chemotherapy agents for medulloblastoma represents a possible novel modality for future treatment of this disease.

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“…Isoflavone genistein exerts its effects by regulation of multiple signaling pathways. We and other investigators have found that isoflavone could significantly inhibit the activation of AR, Akt, and NF-κB in PCa cells and interrupt the crosstalk between these three signaling pathways in vitro [30–35]. By in vivo studies, isoflavone has been found to inhibit prostate tumor growth through inhibition of AR activation and AR downstream gene expression [36, 37].…”

Section: The Role Of Nutraceuticals In the Inhibition Of Pcamentioning

confidence: 99%

Recent progress on nutraceutical research in prostate cancer

Ahmad

Kong

et al. 2013

Cancer Metastasis Rev

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Recently, nutraceuticals have received increasing attention as the agents for cancer prevention and supplement with conventional therapy. Prostate Cancer (PCa) is most frequently diagnosed cancer and second leading cause of cancer-related death in men in US. Growing evidences from epidemiological studies, in vitro experimental studies, animal studies, and clinical trials have shown that nutraceuticals could be very useful for the prevention and treatment of PCa. Several nutraceuticals including isoflavone, indole-3-carbinol, 3,3’-diindolylmethane, lycopene, (-)-epigallocatechin-3-gallate, and curcumin are known to down-regulate the signal transductions in AR, Akt, NF-κB, and other signal transduction pathways which are vital for the development of PCa and the progression of PCa from androgen-sensitive to castrate-resistant PCa. Therefore, nutraceutical treatment in combination with conventional therapeutics could achieve better treatment outcome in prostate cancer therapy. Interestingly, some nutraceuticals could regulate the function of cancer stem cell (CSC) related miRNAs and associated molecules, leading to the inhibition of prostatic CSCs which are responsible for drug-resistance, tumor progression, and recurrence of PCa. Hence, nutraceuticals may serve as powerful agents for the prevention of PCa progression and they could also be useful in combination with chemotherapeutics or radiotherapy. Such strategy could become a promising newer approach for the treatment of metastatic PCa with better treatment outcome by improving overall survival.

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Genistein Sensitizes Bladder Cancer Cells to HCPT Treatment In Vitro and In Vivo via ATM/NF-κB/IKK Pathway-Induced Apoptosis

Cited by 43 publications

References 30 publications

10-Hydroxycamptothecin induces apoptosis in human neuroblastoma SMS-KCNR cells through p53, cytochrome c and caspase 3 pathways

10-Hydroxycamptothecin induces apoptosis in human neuroblastoma SMS-KCNR cells through p53, cytochrome c and caspase 3 pathways

PDE5 inhibitors enhance the lethality of standard of care chemotherapy in pediatric CNS tumor cells

Recent progress on nutraceutical research in prostate cancer

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