Targeting mitochondria for cancer therapy

Hockenbery, David M.

doi:10.1002/em.20552

Cited by 90 publications

(60 citation statements)

References 145 publications

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“…Mitochondria have been considered as anticancer drug targets and have a key function in the regulation of apoptosis. 25) Our results indicated that cladribine caused G 2 /M arrest in MCF-7 cells and that the combination of cladribine and gefitinib or dasatinib led to an accumulation of cells in the G 2 /M phases at the expense of the G 1 phase. Dasatinib induced G 1 arrest in MCF-7 cells.…”

Section: Discussionsupporting

confidence: 49%

Synergistic Activity of an Antimetabolite Drug and Tyrosine Kinase Inhibitors against Breast Cancer Cells

Zhang

Yuan

et al. 2017

Chem. Pharm. Bull.

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Antimetabolite drugs, including the adenosine deaminase inhibitor cladribine, have been shown to induce apoptosis in a variety of cancer cells, and have been widely used in clinical trials of various cancers in conjunction with tyrosine kinase inhibitors (TKIs). Combination treatment with cladribine and gefitinib or dasatinib is expected to have a synergistic inhibitory effect on breast cancer cell growth. Our results demonstrated that the combination treatment had synergistic activity against human breast cancer (MCF-7) cells, enhanced G 2 /M cell arrest and reactive oxygen species (ROS) generation, and increased the loss of mitochondrial membrane potential and cell apoptosis. In addition, the combination treatment decreased Bcl-2 expression. Our results demonstrated that cladribine in combination with gefitinib or dasatinib exerted synergistic anticancer effects on MCF-7 cells by inducing cell cycle arrest, ROS production and apoptosis through the mitochondria-mediated intrinsic pathway.Key words cladribine; gefitinib; dasatinib; breast cancer; combination therapy Breast cancer is the most common malignant tumor and the leading cause of cancer-related deaths in women.1,2) Current treatment for breast cancer includes surgery, radiotherapy and drug therapy, with drug therapy including hormone therapy, chemotherapy and immunotherapy.3,4) The pathogenesis of breast cancer has been studied in-depth, 5) and many drugs have emerged for the treatment of breast cancer, with chemotherapy remaining the mainstay of treatment for breast cancer in addition to surgery. In the clinic, the main chemotherapeutic agents used to treat breast cancer include cisplatin and paclitaxel, docetaxel, curcumin, navelbine, and oxaliplatin. Although these chemotherapy drugs are widely used in the treatment of breast cancer, they often have severe side effects. 6)Recent studies have found that multiple signaling pathways, such as phosphatidylinositol 3-kinase (PI3K) and mitogenactivated protein kinase (MAPK), are involved in breast cancer cell proliferation, and targets of these pathways, such as epidermal growth factor receptor (EGFR), Akt, mammalian target of rapamycin (mTOR), insulin-like growth factor 1 receptor (IGF-1R), human epidermal growth factor receptor-2 (HER2), have become anti-breast cancer drug targets. 7,8) We are known to target anti-breast cancer drugs trastuzumab, lapatinib and so on, but the development of drug resistance in patients has limited their clinical use. With the integration of various disciplines of drug research, the role of multiple targets in biological signaling networks and pathways to achieve appropriate physiological and pathological outcomes has been well studied.9) A growing body of literature has also shown that drug combinations have synergistic anti-cancer effects through the inhibition of these targets. [10][11][12][13][14] In the clinic, combination chemotherapy for breast cancer is widely used, including drugs such as dasatinib and adriamycin, and has shown excellent results. 15)The clinical app...

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Section: Discussionsupporting

confidence: 49%

Synergistic Activity of an Antimetabolite Drug and Tyrosine Kinase Inhibitors against Breast Cancer Cells

Zhang

Yuan

et al. 2017

Chem. Pharm. Bull.

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“…Bcl-2 is a major anti-apoptotic protein which protects cells from a wide variety of apoptotic stimuli (26). By contrast, Bax is a Bcl-2-like protein that binds to and antagonizes the protective effect of Bcl-2, rendering cells more sensitive to apoptosis (27). In the present study, we found that only the level of Bax in H28 cells was significantly elevated by BBI treatment.…”

Section: Discussionsupporting

confidence: 41%

Bowman-Birk protease inhibitor from soybeans enhances cisplatin-induced cytotoxicity in human mesothelioma cells

Kashiwagi

Virgona

Yamada

et al. 2011

Experimental and Therapeutic Medicine

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Abstract. Malignant mesothelioma (MM) is an aggressive cancer with no effective treatment options. Enforced expression of the gap junction (GJ) component connexin 43 (Cx43) increases the sensitivity of MM cells to cisplatin. BowmanBirk protease inhibitor (BBI) induces the restoration of Cx43 in several types of tumor cells. In this study, we examined the capability of BBI to enhance the cytotoxic effect of cisplatin in MM cells via the induction of Cx43. Human MM H28 cells were used. Cell viability was evaluated by a WST-1 assay and proteasomal activity was determined by fluorometric analysis. Protein and mRNA levels were determined by immunoblot analysis and real-time RT-PCR, respectively. GJ function mediated by Cx43 was evaluated using the scrapeloading method. BBI effectively inhibited H28 cell growth in a dose-dependent manner (200-400 µg/ml). In parallel with the growth inhibition, Cx43 levels (mRNA and protein) and GJ function were elevated by BBI treatment. Knockdown of BBI-induced Cx43 by an antisense nucleotide treatment almost cancelled the growth inhibition. BBI enhanced cisplatin-induced cytotoxicity in H28 cells, and down-regulation of Cx43 by the antisense nucleotide treatment abrogated the enhancing effect of BBI. The induction of Cx43 by BBI contributed to Src inactivation and subsequent induction of Bax. Furthermore, an Src inhibitor (SU6656) also enhanced cisplatin-induced cytotoxicity in H28 cells. These results suggest that BBI improves the cytotoxic efficacy of cisplatin in H28 cells via the inhibition of Src signaling.

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“…Bcl-2 inhibits the mitochondrial pathways of apoptosis through local effects at the mitochondrial and endoplasmic reticulum membranes (32). Furthermore, Bcl-2 was reported to be overexpressed in most breast cancer cells (33,34).…”

Section: Discussionmentioning

confidence: 99%

SIRT1 suppresses breast cancer growth through downregulation of the Bcl-2 protein

et al. 2013

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Abstract. Silent mating-type information regulation 2 homologue 1 (SIRT1), a member of the class III histone deacetylase (HDAC) family, is the mammalian ortholog of yeast Sir2. It has been reported to play a key role in a variety of physiological processes such as genomic stability, metabolism, neurogenesis and cell survival. The deacetylase function of SIRT1 has been suggested to play a role in prolonging the life of mammals. However, the suggested functions of SIRT1 as a potential tumor promoter have been challenged by observations of their respective downregulation and upregulation in various types of cancer. Breast cancer patients were included in the present study between 2007 and 2008. Their tumor tissues and paired normal breast tissues were collected and used for evaluation of the expression levels of SIRT1 and Ki67. The effects of SIRT1 on human breast cancer cell lines were also investigated. Immunohistochemistry showed that there is a high correlation between SIRT1 and Ki67 expression. Following treatment with sirtinol (inhibitor of SIRT1), the expression of the prosurvival protein Bcl-2 was markedly decreased in both MCF-7 and MDA-MB-231 cell lines, particularly in MDA-MB-231. Results of the present study revealed that inhibition of SIRT1 activity may be a promising chemotherapeutic strategy against breast cancer.

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Targeting mitochondria for cancer therapy

Cited by 90 publications

References 145 publications

Synergistic Activity of an Antimetabolite Drug and Tyrosine Kinase Inhibitors against Breast Cancer Cells

Synergistic Activity of an Antimetabolite Drug and Tyrosine Kinase Inhibitors against Breast Cancer Cells

Bowman-Birk protease inhibitor from soybeans enhances cisplatin-induced cytotoxicity in human mesothelioma cells

SIRT1 suppresses breast cancer growth through downregulation of the Bcl-2 protein

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