NSC606985, a novel camptothecin analog, induces apoptosis and growth arrest in prostate tumor cells

Tan, Chen; Cai, Li-Qun; Wu, Wenrui; Qiao, Ying; Imperato‐McGinley, Julianne; Chen, Guoqiang

doi:10.1007/s00280-008-0740-8

Cited by 15 publications

(24 citation statements)

References 31 publications

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“…CPT is known to exert killing effects by inducing apoptosis in cancer cells (Tan et al, 2009). To reveal whether miR-125b was involved in CPT-induced apoptosis, we investigated the expression patterns of miR-125b during apoptotic stress after CPT treatment.…”

Section: Mir-125bmentioning

confidence: 99%

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Camptothecin Induces Apoptosis in Cancer Cells via MicroRNA-125b-Mediated Mitochondrial Pathways

Zeng

Zhang²,

Lin³

et al. 2012

Mol Pharmacol

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Camptothecin (CPT) is an effective chemotherapeutic agent for treatment of patients with cancer. The mechanisms underlying CPT-mediated responses in cancer cells are not fully understood. MicroRNA (miRNA) play important roles in tumorigenesis and drug sensitivity. However, the interaction between camptothecin and miRNA has not been previously explored. In this study, we verified that miR-125b was down-regulated in CPTinduced apoptosis in cancer cells and that ectopic expression of miR-125b partially restored cell viability and inhibited cell apoptosis that was induced by CPT. In addition, we demonstrated that CPT induced apoptosis in cancer cells by miR125b-mediated mitochondrial pathways via targeting to the 3Ј-untranslated (UTR) regions of Bak1, Mcl1, and p53. A significant increase in Bak1, Mcl1, and p53 protein levels was detected in response to the treatments of CPT. It is noteworthy that the expression levels of Bak1, Mcl1, and p53 increased in a time-dependent manner and negatively correlated with miR125b expression. It is noteworthy that we revealed that miR125b directly targeted the 3ЈUTR regions of multiple genes in a CPT-induced mitochondrial pathway. In addition, most targets of miR-125b were proapoptotic genes, whereas some of the targets were antiapoptotic genes. We hypothesized that miR125b may mediate the activity of chemotherapeutic agents to induce apoptosis by regulating multiple targets. This is the first report to show that camptothecin induces cancer cell apoptosis via miRNA-mediated mitochondrial pathways. The results suggest that suppression of miR-125b may be a novel approach for the treatment of cancer.

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Section: Mir-125bmentioning

confidence: 99%

“…One of the major modes of action of these chemotherapeutic drugs may be via the activation of apoptosis (Makin and Dive, 2001). Indeed, several researchers have reported that CPT induces apoptosis in various cancer cells (Sá nchez-Alcá zar et al, 2000;Tan et al, 2009). However, the detailed molecular mechanisms are not fully understood.…”

Section: Introductionmentioning

confidence: 99%

Camptothecin Induces Apoptosis in Cancer Cells via MicroRNA-125b-Mediated Mitochondrial Pathways

Zeng

Zhang²,

Lin³

et al. 2012

Mol Pharmacol

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“…To measure gene expression, RT-PCR and real-time PCR were performed as previously described (15,24). Briefly, total cellular RNA was isolated using TriPure reagents, and the level of specified RNAs were quantified using a NanoDrop2000C.…”

Section: Reverse Transcription Pcr (Rt-pcr) and Quantitative Rt-pcrmentioning

confidence: 99%

“…Western blotting was carried out following standard methods with minor modifications (15). Briefly, cells were harvested and total cellular proteins were extracted using a RIPA buffer (25 mM Tris-HCl pH 7.6, 150 mM NaCI, 1% NP-40, 1% sodium deoxycholate, 0.1% SDS).…”

Section: Reverse Transcription Pcr (Rt-pcr) and Quantitative Rt-pcrmentioning

confidence: 99%

“…NSC606985 (NSC), a highly water-soluble camptothecin analog, has recently been demonstrated to produce both caspase-dependent and caspase- independent tumor cell death via differential mechanisms (13,14). In a previous study, we demonstrated the antitumor activity of NSC in prostate cancer cells through the interaction with topoisomerase 1 and an activation of the mitochondrial apoptotic pathway (15). However, the molecular pathway of NSC activation of cell apoptosis in prostate cancer cells remains to be further elucidated.…”

Section: Introductionmentioning

confidence: 99%

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Dissociation of NSC606985 induces atypical ER-stress and cell death in prostate cancer cells

Wang

Zhao

et al. 2016

International Journal of Oncology

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Abstract. Castration-resistant prostate cancer (CRPC) is a major cause of prostate cancer (Pca) death. Chemotherapy is able to improve the survival of CRPC patients. We previously found that NSC606985 (NSC), a highly water-soluble camptothecin analog, induced cell death in Pca cells via interaction with topoisomerase 1 and activation of the mitochondrial apoptotic pathway. To further elucidate the role of NSC, we studied the effect of NSC on ER-stress and its association with NSC-induced cell death in Pca cells. NSC produced a timeand dose-dependent induction of GRP78, CHOP and XBP1s mRNA, and CHOP protein expression in Pca cells including DU145, indicating an activation of ER-stress. However, unlike conventional ER-stress in which GRP78 protein is increased, NSC produced a time-and dose-dependent U-shape change in GRP78 protein in DU145 cells. The NSC-induced decrease in GRP78 protein was blocked by protease inhibitors, N-acetyl-L-leucyl-L-leucylnorleucinal (ALLN), a lysosomal protease inhibitor, and epoxomicin (EPO), a ubiquitin-protease inhibitor. ALLN, but not EPO, also partially inhibited NSC-induced cell death. However, both 4-PBA and TUDCA, two chemical chaperons that effectively reduced tunicamycin-induced ER-stress, failed to attenuate NSC-induced GRP78, CHOP and XBP1s mRNA expression and cell death. Moreover, knockdown of NSC induction of CHOP expression using a specific siRNA had no effect on NSC-induced cytochrome c release and NSC-induced cell death. These results suggest that NSC produced an atypical ER-stress that is dissociated from NSC-induced activation of the mitochondrial apoptotic pathway and NSC-induced cell death in DU145 prostate cancer cells.

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Nuclear translocation of dihydrofolate reductase is not a pre-requisite for DNA damage induced apoptosis

Yuan

Huang²,

Zhou

et al. 2009

Apoptosis

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Dihydrofolate reductase (DHFR) is a key enzyme for the synthesis of thymidylate, and therefore, of DNA. By applying subcellular proteomic analysis, we identified that the DHFR protein was translocated from cytoplasm into the nucleus when apoptosis was induced by NSC606985, a camptothecin analogue. The nuclear translocation of DHFR protein during apoptosis was independent of the cellular context, but it was more sensitive in cell death induction by DNA damaging agents such as doxorubicin, etoposide and ultraviolent radiation than endoplasmic reticulum stressors (brefeldin-A and tunicamycin) and anti-microtubule agents (paclitaxel and nocodozole). The addition of methotrexate almost completely blocked the nuclear translocation of DHFR protein. Further investigations showed that the nuclear translocation of DHFR was not a pre-requisite for DNA damage induced apoptosis. Therefore, its potential biological significance remains to be further explored.

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NSC606985, a novel camptothecin analog, induces apoptosis and growth arrest in prostate tumor cells

Cited by 15 publications

References 31 publications

Camptothecin Induces Apoptosis in Cancer Cells via MicroRNA-125b-Mediated Mitochondrial Pathways

Camptothecin Induces Apoptosis in Cancer Cells via MicroRNA-125b-Mediated Mitochondrial Pathways

Dissociation of NSC606985 induces atypical ER-stress and cell death in prostate cancer cells

Nuclear translocation of dihydrofolate reductase is not a pre-requisite for DNA damage induced apoptosis

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