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Systemic chemotherapy in combination with local intervention through surgery and radiotherapy are effective treatments for breast cancers. Chemotherapy is often used in patients with early signs of disease to effectively shrink the tumor and prevent metastasis before surgical excision of the tumor. However, relapse occurs in some of these patients due to the presence of remnant cancer cells that are resistant to chemotherapy. These cancer cells may acquire additional resistance mechanisms resulting in multi-drug resistance and treatment failure. Aggressive tumors show inherently poor sensitivity to chemotherapeutics. Studies primarily based on cell culture models have identified mechanisms of chemo-resistance. These mechanisms include alterations in drug accumulation, increased drug metabolism, altered DNA damage response, evasion of cell-death and decreased ceramide accumulation. In animal models of cancer, additional complexity arises from signaling cross-talk among the cancer cells, stroma, extracellular matrix and the vasculature in the tumor microenvironment that contribute to the development of multi-drug resistance. Cytokines, chemokines and growth factors secreted into the tumor microenvironment represent a hurdle to successful chemotherapy by making the tumors inherently resistant and contributing to development of additional resistance. We examined the mechanism by which extracellular lysophosphatidate (LPA), which is produced by the secreted enzyme, autotaxin (ATX), contributes to multi-drug resistance using breast, thyroid, liver and lung cancer cells. LPA acts through its G-protein coupled receptor, LPA1-6, to promote survival and proliferation in cancers. We discovered that LPA increased the stability and nuclear localization of the transcription factor Nuclear Factor, Erythroid 2-Like 2 or Nrf2. Nrf2, a master regulator of the antioxidant response, promotes resistance to chemotherapeutics through increased metabolism, conjugation and export of drugs from the cell. We showed that LPA, through the activation of LPA1 receptors and phosphatidylinositol 3-kinase (PI3K), increased Nrf2 stabilization and the expression of multi-drug resistance transporters (MDRT) and antioxidant genes. LPA increased the efflux of substrates of the MDRT, which includes chemotherapeutics such as doxorubicin. Consequentially, LPA protected cancer cells from doxorubicin- and etoposideinduced apoptosis. We tested these results in vivo using a syngeneic 4T1 breast cancer model. Blocking LPA production with ONO-8430506, a competitive ATX inhibitor, decreased the expression of Nrf2 and Nrf2-regulated genes in breast tumors. Combining 4 mg/kg doxorubicin every third day with 10 mg/kg ONO- 8430506 every day decreased tumor growth and metastasis to lungs and liver by >70%, whereas doxorubicin alone had no significant effect on tumor growth. Additionally, we show increased expression of Nrf2 in the primary tumors of breast cancer patients, who have a recurrence following surgery and chemotherapy. We also demonstrate a novel concept of chemotherapy-induced increases in inflammation and ATX production as a mediator of resistance to oxidative damage in the 4T1 tumors. Increased expression of Nrf2 and its targets were also observed in tamoxifen-treated breast cancer cells and tumors. Inhibition of ATX overcomes this vicious cycle of inflammation, LPA production and resistance to oxidative damage. Finally, we examined another aspect of LPA signaling that contributes to increased resistance to chemotherapeutics. This involves increased activation and expression of sphingosine kinase 1 (SK1), which results in formation of sphingosine 1-phosphate (S1P) in the cells. LPA-induced translocation of SK1 to membranes, which constitutes an activation step, is higher in doxorubicin-resistant cancer cells when compared to their isogenic controls. Additionally, the doxorubicin-resistant cancer cells have increased expression of the MDRT and S1P receptors. We propose that extracellular LPA coordinates S1P signaling in cancer cells. This is through activation of SK1, secretion of S1P through the MDRT and increased signaling of secreted S1P through the S1P receptors. Overall, our studies have demonstrated a potentially important role for LPA signaling in increasing resistance to chemotherapies and development of multi-drug resistance. This is through the increased expression of Nrf2 and transcription of antioxidant and MDRT genes. Our study also provides a practical strategy for targeting LPA signaling in cancers by blocking LPA production with ATX inhibitors. There are no ATX inhibitors in the clinic. Inhibition of ATX could be a useful strategy in improving the efficacy of existing cancer therapies and to prevent the development of chemo-resistance in patients.
Biological Mechanisms and the Advancing Approaches to Overcoming Cancer Drug Resistance, Volume 12, discusses new approaches that are being undertaken to counteract tumor plasticity, understand and tackle the interactions with the microenvironment, and disrupt the rewiring of malignant cells or bypass biological mechanism of resistance by using targeted radionuclide therapies. This book provides a unique opportunity to the reader to understand the fundamental causes of drug resistance and how different approaches are applied. It is a one-stop-shop to understand why it is so difficult to treat cancer, and why only a very few patients respond to therapy and a significant portion develop resistance. Despite a rapid development of more effective anti-cancer drugs and combination therapies, cancer remains the leading cause of lethality in the developed world. The main reason for this is the ability of heterogeneous subpopulations of tumor cells interacting with constantly evolving tumor microenvironment to resist elimination and eventually, trigger cancer relapse. In this book, experts review current concepts explaining molecular and biological mechanisms of cancer drug resistance and discussing advancing approaches for overcoming these therapeutic challenges. - Provides the most updated knowledge on the mechanisms of cancer drug resistance and the emerging therapeutic approaches reviewed by experts in the field - Brings detailed analyses of most important recently reported developments related to drug resistance and their relevance to overcoming it in cancer patients - Discusses in-depth molecular mechanisms and novel concepts of cancer resistance to conventional and advanced therapies
Melanoma - Current Clinical Management and Future Therapeutics serves as an advanced course in melanoma or an addendum to further polish expertise. Sections of the book include a thorough introduction on epidemiology and disease, the current surgical management of melanoma and lymph node dissection, immunotherapy along with drug toxicities and emerging research topics, like RAGE and autotaxin, that have potential therapeutic applications. The chapters in this book explore the most common subtype of melanoma, cutaneous disease, as well as a rare form, acral lentiginous melanoma and even canine tumors. Experts from around the globe contributed chapters, most of which have visual illustrations to depict aspects of disease management and therapy, allowing readers to grasp the advanced concepts presented.
Amazing anticancer therapy advancements have been made in the last decade due to tremendous innovations. Nonetheless, drug resistance remains a major challenge that limits the effectiveness of anticancer therapies, causing cancer recurrence and metastasis and being a major cause of cancer-related death. Drug resistance can be caused by complex molecular mechanisms such as gene mutations, epigenetic dysregulation, microenvironment alterations, etc. Many clinical strategies, including combination therapies and epigenetic drugs, have been used to avoid or reverse drug resistance effectively. However, the progression of cancers (in patients under treatment) or the lack of response of cancer patients indicate that current approaches to overcome resistance are far from sufficient, and more work is needed.
Receptor Tyrosine Kinase: Structure, Functions and Role in Human Disease, for the first time, systematically covers the shared structural and functional features of the RTK family. Receptor Tyrosine Kinases (RTKs) play critical roles in embryogenesis, normal physiology and several diseases. And over the last decade they have become the Number 1 targets of cancer drugs. To be able to conduct fundamental research or to attempt to develop pharmacological agents able to enhance or intercept them, it is essential first to understand the evolutionary origin of the 58 RTKs and their roles in invertebrates and in humans, as well as downstream signaling pathways. The assembly of chapters is written by experts and underscores commonalities between and among the RTKs. It is an ideal companion volume to The Receptor Tyrosine Kinase: Families and Subfamilies, which proceeds, family by family through all of the specific subfamilies of RTKs, along with their unique landmarks.
Ovarian carcinoma continues to be responsible for more deaths than all other gynecologic malignancies combined, due to a continued inability to achieve detection of early (rather than advanced) stage disease and the lack of effective tumor-specific therapeutics. Ovarian carcinogenesis, invasion, and metastatic dissemination require a complex cascade of interrelated genetic, molecular, and biochemical events that regulate the neoplastic transition of normal ovarian surface epithelium. This updated second edition includes exciting new advances in ovarian cancer detection and treatment and provides an analysis of current research into aspects of malignant transformation, growth control, and metastasis. A more detailed understanding of these processes may ultimately translate into the development of novel approaches for the detection and control of ovarian cancer.
This new olive oil handbook provides a wealth of detail about the analysis and properties of olives and their oil. It covers technological aspects and biochemistry, a description of detailed techniques, and an analysis of olive oil from the standpoint of general methodology.
Sphingolipids are fundamental to the structures of cell membranes, lipoproteins, and the stratum cornea of the skin. Many complex sphingolipids, as well as simpler sphingoid bases and derivatives, are highly bioactive as extra- and intracellular regulators of growth, differentiation, migration, survival, senescence, and numerous cellular responses to stress. This book reviews exciting new developments in sphingolipid biology/sphingolipidology that challenge our understanding of how multicellular organisms grow, develop, function, age, and die.