Regulating TRAIL Receptor-Induced Cell Death at the Membrane: A Deadly Discussion

Author(s):

Sarah Shirley, Alexandre Morizot and Olivier MicheauPages 311-323 (13)

Abstract:

The use of TRAIL/APO2L and monoclonal antibodies targeting TRAIL receptors for cancer therapy holds great promise, due to their ability to restore cancer cell sensitivity to apoptosis in association with conventional chemotherapeutic drugs in a large variety of tumors. TRAIL-induced cell death is tightly regulated right from the membrane and at the DISC (Death-Inducing Signaling Complex) level. The following patent and literature review aims to present and highlight recent findings of the deadly discussion that determines tumor cell fate upon TRAIL engagement.

Keywords:

chemotherapy, death domain, death effector domain, DISC, FADD, c-FLIP,, scaffold, TRAIL, TRAIL-R4, APO2-L

Affiliation:

INSERM, U866, Dijon, F- 21079 France; Faculty of Medicine and Pharmacy, University of Bourgogne, Dijon, F-21079 France.

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Circulatory Estrogen Level Protects Against Breast Cancer in Obese Women

Author(s):

Zsuzsanna SubaPages 154-167 (14)

Abstract:

Literary data suggest apparently ambiguous interaction between menopausal status and obesity-associated breast cancer risk based on the principle of the carcinogenic capacity of estrogen. Before menopause, breast cancer incidence is relatively low and adiposity is erroneously regarded as a protective factor against this tumor conferred by the obesity associated defective estrogen-synthesis. By contrast, in postmenopausal cases, obesity presents a strong risk factor for breast cancer being mistakenly attributed to the presumed excessive estrogen-production of their adipose-tissue mass. Obesity is associated with dysmetabolism and endangers the healthy equilibrium of sexual hormone-production and regular menstrual cycles in women, which are the prerequisites not only for reproductive capacity but also for somatic health. At the same time, literary data support that anovulatory infertility is a very strong risk for breast cancer in young women either with or without obesity. In the majority of premenopausal women, obesity associated insulin resistance is moderate and may be counteracted by their preserved circulatory estrogen level. Consequently, it is not obesity but rather the still sufficient estrogen-level, which may be protective against breast cancer in young adult females. In obese older women, never using hormone replacement therapy (HRT) the breast cancer risk is high, which is associated with their continuous estrogen loss and increasing insulin-resistance. By contrast, obese postmenopausal women using HRT, have a decreased risk for breast cancer as the protective effect of estrogen-substitution may counteract to their obesity associated systemic alterations. The revealed inverse correlation between circulatory estrogen-level and breast cancer risk in obese women should advance our understanding of breast cancer etiology and promotes primary prevention measures. New patents recommend various methods for the prevention and treatment of obesity-related systemic disorders and the associated breast cancer.

Keywords:

Androgen, breast cancer risk, estrogen, insulin resistance, menopause, metabolic syndrome, obesity, type-2 diabetes, visceral adiposity

Affiliation:

National Institute of Oncology, Surgical and Molecular Tumor Pathology Centre, Address: H-1122 Rath Gyorgy str. 7-9, Budapest, Hungary.

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Causal Therapy of Breast Cancer Irrelevant of Age, Tumor Stage and ER-Status: Stimulation of Estrogen Signaling Coupled With Breast Conserving Surgery

Author(s):

Zsuzsanna SubaPages 1-13 (13)

Abstract:

Background. Results of long-term studies justify that the rate of breast cancer recurrence and tumor-related mortality remains quite unpredictable, regardless of the use of any current therapeutic measures.

Objective. Since the application of standard therapies, such as surgery, radiation, chemotherapy and antiestrogen administration does not work as might be expected; our therapeutic practice requires thorough rethinking.

Method. Published long-term therapeutic results on breast cancer cases were analyzed in correlation with stage at diagnosis, ER-status of tumors and patients’ age. The effectiveness of current therapeutic measures was also compared by estimating the rate of tumor-free survival, breast cancer recurrence and breast cancer-specific mortality.

Results. Diagnosis and treatment of breast cancer at an early stage cannot improve the rate of tumor-free survival. Poor differentiation of tumors, ER-negativity in particular, defines poor prognosis even after applying aggressive therapies. In patients treated with in-situ breast cancer, the recurrence-rate of invasive tumor increased directly with ageing irrespective of tumor size or ER-status at diagnosis. Women who underwent lumpectomy without adjuvant radiation or chemotherapy exhibited significantly better overall and breast cancer specific survival rates than those receiving mastectomy, regardless of stage and ER-status of tumors. Antiestrogen treatment exhibited unforeseeable effectiveness even on targeted ER-positive tumors. Recent patents propose the detection of ESR1-gene amplification or restoration of ER-alpha expression for prediction of effective antiestrogen treatment, suggesting a crucial inhibitory role of estrogen-signaling against tumor-growth.

Conclusion. Estradiol-induced upregulation of estrogen signaling coupled with sparing of the estrogen-rich mammary fatpad are the most effective strategies against breast cancer.

Keywords:

Antiestrogen resistance, breast cancer risk, DNA-stabilization, estradiol therapy, estrogen signaling, lumpectomy, mastectomy, protective adipocytes, radiation therapy

Affiliation:

National Institute of Oncology Surgical and Molecular Tumor Pathology Centre Address: H-1122, Ráth György str. 7-9 Budapest, Hungary

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Aldo-Keto Reductase Family 1 Member B10 Inhibitors: Potential Drugs for Cancer Treatment

Author(s):

Li Huang, Rongzhang He, Weihao Luo, Yuan-Shan Zhu, Jia Li, Tan Tan, Xi Zhang, Zheng Hu and Dixian LuoPages 184-196 (13)

Abstract:

Cytosolic NADPH-dependent reductase AKR1B10 is a member of the aldo-keto reductase (AKR) superfamily. This enzyme is normally expressed in the gastrointestinal tract. However, it is overexpressed in many solid tumors, such as hepatocarcinoma, lung cancer and breast cancer. AKR1B10 may play a role in the formation and development of carcinomas through multiple mechanisms including detoxification of cytotoxic carbonyls, modulation of retinoic acid level, and regulation of cellular fatty acid synthesis and lipid metabolism. Studies have suggested that AKR1B10 may be a useful biomarker for cancer diagnosis and a potential target for cancer treatment. Over the last decade, a number of AKR1B10 inhibitors including aldose reductase inhibitors (ARIs), endogenous substances, natural-based derivatives and synthetic compounds have been developed, which could be novel anticancer drugs. This review provides an overview on related articles and patents about AKR1B10 inhibitors, with a focus on their inhibition selectivity and mechanism of function.

Keywords:

AKR1B10, Aldo-keto reductase, ARL-1, cancer, chemoresistance, inhibitors.

Affiliation:

Translational Medicine Institute, National & Local Joint Engineering Laboratory for High-through Molecular Diagnosis Technology, Collaborative Research Center for Postdoctoral Mobile Stations of Central South University, Affiliated the First Peoples Hospital of Chenzhou of University of South China, Chenzhou 432000, P.R.China.

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