Apoptosis-Modulating Drugs for Improved Cancer Therapy

Ocker, Matthias; Höpfner, Michael

doi:10.1159/000336875

Cited by 78 publications

(62 citation statements)

References 155 publications

(161 reference statements)

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“…Multiple mechanisms, such as enhanced cell survival signals and autophagy and/or suppressed apoptosis, are involved in chemoresistance (9,10,41,42). While MUC1 expression is increased in cancer cells and MUC1 has served as an immunotherapy target in different tumor types, the role of MUC1 in acquired chemoresistance has not been studied.…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, lung cancer cells with resistance to one drug may also become resistant to other anticancer therapeutics (4)(5)(6)(7)(8). It is believed that chemotherapeutics kill cancer cells mainly through the activation of apoptosis; and apoptosis resistance substantially contributes to chemoresistance (9,10). Thus, elucidating the mechanisms for apoptosis resistance and acquired chemoresistance is highly significant for improving the survival of lung cancer patients.…”

Section: Introductionmentioning

confidence: 99%

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A signaling pathway consisting of miR-551b, catalase and MUC1 contributes to acquired apoptosis resistance and chemoresistance

Xu¹,

Wells²,

Padilla³

et al. 2014

Carcinogenesis

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Acquired chemoresistance is a major challenge in cancer therapy. While the oncoprotein Mucin-1 (MUC1) performs multiple roles in the development of diverse human tumors, whether MUC1 is involved in acquired chemoresistance has not been determined. Using an acquired chemoresistance lung cancer cell model, we show that MUC1 expression was substantially increased in cells with acquired apoptosis resistance (AR). Knockdown of MUC1 expression effectively increased the sensitivity of these cells to the apoptotic cytotoxicity of anticancer therapeutics, suggesting that MUC1 contributes to acquired chemoresistance. Decreased catalase expression and increased cellular reactive oxygen species (ROS) accumulation were found to be associated with MUC1 overexpression. Scavenging ROS with butylated hydroxyanisole or supplying exogenous catalase dramatically suppressed MUC1 expression through destabilizing MUC1 protein, suggesting that reduced catalase expression mediated ROS accumulation is accounted for MUC1 overexpression. Further, we found that increased miR-551b expression in the AR cells inhibited the expression of catalase and potentiated ROS accumulation and MUC1 expression. Finally, by manipulating MUC1 expression, we found that MUC1 promotes EGFR-mediated activation of the cell survival cascade involving Akt/c-FLIP/COX-2 in order to protect cancer cells from responding to anticancer agents. Thus, our results establish a pathway consisting of miR-551b/catalase/ ROS that results in MUC1 overexpression, and intervention against this pathway could be exploited to overcome acquired chemoresistance.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A signaling pathway consisting of miR-551b, catalase and MUC1 contributes to acquired apoptosis resistance and chemoresistance

Xu¹,

Wells²,

Padilla³

et al. 2014

Carcinogenesis

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“…Among several death mechanisms, the induction of apoptosis is the most important method in the treatment of cancers, as cancer is one of the scenarios where too little apoptosis occurs, resulting in cancer cells that will not die, and defects at any point along the apoptosis pathways lead to the malignant transformation of the affected cells, tumor metastasis and resistance to anticancer drugs (16,17). Therefore, a number of apoptosis-modulating drugs have been developed (18). Previously, we designed and synthesized FPDHP as a phenanthroline derivative, and demonstrated its topoisomerase I inhibitory activity and cytotoxicity against several human cancer cell lines (12).…”

Section: Discussionmentioning

confidence: 99%

FPDHP, a novel anticancer agent, induces cell detachment and caspase-dependent apoptosis in Caki cells

Park

Kim

et al. 2014

International Journal of Molecular Medicine

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Abstract. The inhibition of topoisomerase can suppress the growth of cancer cells and induce apoptosis. The aim of this study was to evaluate the anticancer effects and mechanisms of action of a novel topoisomerase inhibitor, 4-(furan-2-yl)-2-(pyridin-2-yl)-5,6-dihydro-1,10-phenanthroline (FPDHP). FPDHP suppressed the growth of Caki, A549, HT29 and MDA-MB-231 cells, and induced caspase-dependent apoptosis in the Caki cells. In particular, FPDHP also induced caspase-dependent apoptosis and the downregulation of the protein expression levels of cellular FLICE-like inhibitory protein (cFLIP) and the phosphorylation of Akt in Caki cells. Notably, the overexpression of cFLIP, but not that of Akt, in part, blocked the FPDHP-mediated apoptosis in Caki cells. In addition, FPDHP was further shown to induce the caspase-independent detachment of Caki cells from the culture dish; higher populations of apoptotic cells were observed in the detached cells than in the attached cells. To the best of our knoweledge, these results collectively demonstrate for the first time that FPDHP has a killing effect on Caki cells, which is mediated through both caspase-dependent apoptosis and caspase-independent cell detachment.

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“…[1][2][3][4][5] Apoptosis is an important pathogenic mechanismin solidary tumor, 6 which is characterized by morphological changes such as cell shrinkage, chromatin condensation and fragmentation of DNA. Cisplatin treatment in vivo and in vitro results in apoptosis of cancer cells, which usually in dose-and time-dependent manner.…”

Section: Introductionmentioning

confidence: 99%

MAPK/ERK Activation Sensitizes MKN-28 Cells to Cisplatin-Induced Apoptosis

Zhang¹,

Liang²,

Zhang³

et al. 2015

Cancer Stud Mol Med Open J

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Cisplatin as a highly potent cytotoxic agent was widely used in the chemotherapy of gastric cancer. It kills cancer cells by inducing apoptosis. The Extracellular signal-regulated kinase (ERK) signaling pathway plays an important role in proliferation and survival. However, its roles in apoptosis vary. This study focused on the role of ERK in cisplatin-induced apoptosis in a stomach cancer cell line, MKN-28 cells. We found that cisplatin treatment substantially activated ERK, which was prevented by MEK inhibitor U0126. Transient transfection of MKN-28 cells with Constitutively Active-MEK1 (CA-MEK1) elevated cisplatin-induced apoptosis comparing with Dominant Negative-MEK1 (DN-MEK1). Cisplatin-induced ERK activation up-regulates pro-apoptotic gene BAK, whereas down-regulates anti-apoptotic gene BCL-2. Knocking down BCL-2 with siRNA sensitizes MKN-28 cells to the toxicity of cisplatin. These results suggested that (1) ERK activation is required for the cisplatin-induced apoptosis in MKN-28 cells; and (2) ERK mediates apoptosis by BCL-2.

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Apoptosis-Modulating Drugs for Improved Cancer Therapy

Cited by 78 publications

References 155 publications

A signaling pathway consisting of miR-551b, catalase and MUC1 contributes to acquired apoptosis resistance and chemoresistance

A signaling pathway consisting of miR-551b, catalase and MUC1 contributes to acquired apoptosis resistance and chemoresistance

FPDHP, a novel anticancer agent, induces cell detachment and caspase-dependent apoptosis in Caki cells

MAPK/ERK Activation Sensitizes MKN-28 Cells to Cisplatin-Induced Apoptosis

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