Table of Contents

Volume 13, Issue 1

  January 1, 2012

  Pages 1 - 60

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 Issue Catalogue (MARC XML)

REVIEWS

Open Access Article

Personalized therapy in endometrial cancer: Challenges and opportunities

Shannon N. Westin and Russell R. Broaddus
Pages 1 - 13
http://dx.doi.org/10.4161/cbt.13.1.18438
Abstract | Full Text | PDF

Early stage endometrial cancer is generally curable. However, progress in the treatment of advanced and recurrent endometrial cancer has been limited. This has led to a shift from the use of traditional chemotherapeutic agents and radiotherapy regimens to the promising area of targeted therapy, given the large number of druggable molecular alterations found in endometrial cancer. To maximize the effects of directed targeted therapy, careful molecular characterization of the endometrial tumor is necessary. This represents an important difference in the use of targeted therapy vs. traditional chemotherapy or radiation treatment. This review will discuss relevant pathways to target in endometrial cancer as well as the challenges that arise during development of a personalized oncology approach.

Open Access Article

Tumor microenvironment and breast cancer progression: A complex scenario

Antonia Artacho-Cordón, Francisco Artacho-Cordón, Sandra Ríos-Arrabal, Irene Calvente and María Isabel Núñez
Pages 14 - 24
http://dx.doi.org/10.4161/cbt.13.1.18869
Abstract | Full Text | PDF

It is now widely accepted that the development and progression of a tumor toward the malignant phenotype is highly dependent on interactions between tumor cells and the tumor microenvironment. Different components of the tumor microenvironment may have stimulatory or inhibitory effects on tumor progression by regulating the gene expression repertoire in tumor cells and stromal cells.

This review analyzes novel research findings on breast cancer progression, discussing acquisition of the metastatic phenotype in breast disease in relation to different aspects of cross-talk among components of the tumor microenvironment. Knowledge of the interaction of all of these factors would contribute to elucidating the mechanisms that disrupt regulatory/signaling cascades and downstream effects in breast cancer.




RESEARCH PAPERS

Open Access Article

Inhibition of the Rho/ROCK pathway enhances the efficacy of cisplatin through the blockage of hypoxia-inducible factor-1α in human ovarian cancer cells

Tsuyoshi Ohta, Toshifumi Takahashi, Tae Shibuya, Mitsuyoshi Amita, Noriko Henmi, Kazuhiro Takahashi and Hirohisa Kurachi
Pages 25 - 33
http://dx.doi.org/10.4161/cbt.13.1.18440
Abstract | Full Text | PDF

Rho, a Ras-related small GTPase, and Rho-associated coiled coil-containing protein kinase (Rho kinase, ROCK1 and ROCK2) are key regulators of focal adhesion, actomyosin contraction, and thus cell motility. Rho/ROCK kinases also play roles in proliferation, differentiation, apoptosis and oncogenic transformation. In the present study, we have shown that Rho/ROCK pathway inhibition by fasudil, an orally administered inhibitor of Rho kinases, enhanced cisplatin-induced growth inhibition and apoptosis in human ovarian cancer cell lines. Fasudil inhibited hypoxia inducible factor (HIF)-1α protein expression. Knockdown of RhoA, ROCK1 or ROCK2 also attenuated the expression of HIF-1α. Furthermore, knockdown of HIF-1α using small interfering RNA enhanced cisplatin-induced growth inhibition and apoptosis as did inhibition of the Rho/ROCK pathway by fasudil, the Rho/ROCK inhibitor Y27632, or by Rho/ROCK knockdown. Therefore, the Rho/ROCK pathway may modulate HIF-1α signal transduction and blockade of Rho/ROCK enhances the efficacy of cisplatin by inhibiting HIF-1α in ovarian cancer cells. Our findings suggested that the Rho/ROCK pathway may be a new target for molecular targeting therapies against ovarian cancer.

Open Access Article

Pharmacologic synergy between dual phosphoinositide-3-kinase and mammalian target of rapamycin inhibition and 5-Fluorouracil in PIK3CA mutant gastric cancer cells

Bhaskar Bhattacharya, Mohamed Akram, Indirikumar Balasubramanian, Kimberley K.Y. Tam, King X. Koh, Mei Q. Yee and Richie Soong
Pages 34 - 42
http://dx.doi.org/10.4161/cbt.13.1.18437
Abstract | Full Text | PDF

Phosphoinositide-3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitors are an emerging class of anti-cancer agents. Here, we tested the hypothesis that the dual PI3K/mTOR inhibitor, PI103, could synergize with the chemotherapeutic agent, 5-fluorouracil (5-FU) by inhibiting E2F1, thymidylate synthase (TS) and enhancing DNA damage. Drug combination effects were assessed in gastric cancer cells using the median-effect equation. The specific effects of inhibition of E2F1 and PIK3CA were examined by siRNA, and mTOR by rapamycin exposure. Protein expression and apoptosis pre- and post-treatment was measured using standard methods. PI103 and 5-FU was synergistic in 3 out of 5 gastric cancer cell lines tested. Synergy was associated with PI3KCA mutation, reduced TS and E2F1 protein levels, increased H2AX phosphorylation and apoptosis. E2F1 siRNA enhanced sensitivity to 5-FU only in cells displaying synergy. Excess thymidine exposure converted synergism to antagonism in all cells. Inhibition of PI3K and mTOR alone enhanced 5-FU cytotoxicity in only 2 out of 3 cell lines that displayed synergy each. In AGS cells, PI3K inhibition alone enhanced 5-FU sensitivity as much as dual PI3K/mTOR inhibition. In HGC27 cells, dual inhibition increased 5-FU sensitivity more than single PI3K or mTOR inhibition. Combined PI103 and 5-FU treatment reduced in vivo tumor growth more than treatment with single agents. PI3K/mTOR inhibitors can enhance 5-FU cytotoxicity in vitro and in vivo, especially in PIK3CA mutant tumor cells. Dual, rather than single, PI3K/mTOR inhibitors may combine better with 5-FU due to cellular heterogeneity in sensitivity to PI3K and mTOR inhibition.

Open Access Article

Inhibition of metadherin sensitizes breast cancer cells to AZD6244

Xiaoli Kong, Meena S. Moran, Yuhan Zhao and Qifeng Yang
Pages 43 - 49
http://dx.doi.org/10.4161/cbt.13.1.18868
Abstract | Full Text | PDF

The development of systemic therapy drug resistance for breast cancer treatment is an ongoing problem, thus, so are the potential molecular mechanisms of it. AZD6244 is a novel ATP-uncompetitive inhibitor to MAP/ERK kinase (MEK) 1/2 which has been demonstrated to be potent, selective and safe in the clinical trials and previous studies. However, the precise role of resistance to AZD6244 is largely unknown. We and other groups have reported that the novel oncogene Metadherin (MTDH) is associated with multiple drug resistance, but there is no report about its role in treatment of AZD6244. Here we report that the resistance to AZD6244 can be reserved by downregulating MTDH in breast cancer cell lines. When the MTDH was downregulated, the breast cancer cells exhibited a significantly increased sensitivity to AZD6244 as measured by MTT assay. After treated with AZD6244 the MTDH-knockdown cells showed more apoptosis rate and growth inhibition. We also showed that knockdown of MTDH cannot only increase expression of FOXO3a but also activate it by promoting its translocation via MTDH/ERK1/2/FOXO3a pathway rather than MTDH/AKT/FOXO3a pathway. In conclusion knockdown MTDH can enhance the breast cancer cells sensitivity to AZD6244 via regulating the expression and activity of FOXO3a. These indicate us that MTDH is a candidate marker to predict the clinical efficacy of AZD6244 and targeting MTDH could overcome the resistance to AZD6244 in breast cancer cells.

Open Access Article

Increased apoptosis in cancer cells in vitro and in vivo by ceramides in transferrin-modified liposomes

Alexander Koshkaryev, Aleksandr Piroyan and Vladimir P. Torchilin
Pages 50 - 60
http://dx.doi.org/10.4161/cbt.13.1.18871
Abstract | Full Text | PDF

Lysosomes are a promising therapeutic target for induction apoptosis in cancer cells due to lysosomal membrane permeabilization (LMP) leading to leakage of hydrolytic enzymes, especially the cathepsins, into the cytoplasm. We hypothesized that with the modification of the ceramide-loaded liposomes with transferrin (Tf), we would achieve both tumor targeting and increased delivery of lysosome-destabilizing agents, such as ceramides to lysosomes, to initiate LMP-induced apoptosis.

We prepared Tf-modified (TL) and plain (PL) liposomes loaded with short (C6) or long (C16) N-acyl chain ceramides. Uptake, intracellular localization of liposomes, stability of the lysosomal membrane and release of cathepsin D were investigated on Hela cells by fluorescence microscopy and flow cytometry. Apoptosis was evaluated by binding of fluorescently-labeled Annexin V. Antitumor and pro-apoptotic effects of C6Cer-loaded Tf-liposomes were demonstrated in vivo in an A2780-ovarian carcinoma xenograft mouse model.

TL were internalized specifically via the TfR-dependent endocytic pathway and localized within the endosome-lysosomal compartment. Ceramide-loaded Tf-liposomes significantly increased apoptosis compared with ceramide-free and ceramide-loaded non-modified liposomes. The treatment of cancer cells with TL led to increased LMP and cytoplasmic relocation of the intralysosomal cathepsin D. A strong antitumor and pro-apoptotic effect of C6Cer-loaded TL was also demonstrated in vivo in an A2780-ovarian carcinoma xenograft mouse model.

The lysosomal accumulation of ceramides delivered by Tf-liposomes initiates the permeabilization of the lysosomal membranes required for the release of lysosomal cathepsins into the cytoplasm and initiation of the cancer cell apoptosis both in vitro and in vivo.