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The Role of Turmeric As an Adjuvant Therapeutic for Osteolytic Breast Cancer Bone Metastases

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The Role of Turmeric As an Adjuvant Therapeutic for Osteolytic Breast Cancer Bone Metastases THE ROLE OF TURMERIC AS AN ADJUVANT THERAPEUTIC FOR OSTEOLYTIC BREAST CANCER BONE METASTASES Item Type text; Electronic Thesis Authors Lukefahr, Ashley Leigh Publisher The University of Arizona. Rights Copyright © is held by the author. Digital access to this material is made possible by the College of Medicine - Phoenix, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author. Download date 01/10/2021 01:11:39 Link to Item http://hdl.handle.net/10150/531833 THE ROLE OF TURMERIC AS AN ADJUVANT THERAPEUTIC FOR OSTEOLYTIC BREAST CANCER BONE METASTASES A Thesis submitted to the University of Arizona College of Medicine ‐‐ Phoenix in partial fulfillment of the requirements for the Degree of Doctor of Medicine Ashley Leigh Lukefahr Class of 2015 Mentor: Janet L Funk, MD, FACP Acknowledgements Thank you to Jen Frye, Minwha Lee, and Guadalupe Barrera for their assistance in the completion of this work. This work was supported by the National Institutes of Health‐funded T32 Arizona Complementary and Alternative Medicine Research Training Program (ACAMTRP). The content is solely the responsibility of the authors and does not necessarily represent the official views of The University of Arizona or the National Institutes of Health. Abstract Zoledronic acid (ZA), the gold standard treatment for breast cancer‐derived osteolytic bone lesions, induces apoptosis in mature osteoclasts. Curcumin, a plant‐dervied component of turmeric (Curcuma longa), inhibits osteoclast differentiation. This study aimed to determine the in vitro and in vivo effects of ZA and curcuminoids, alone and combined, on osteoclast differentiation and survival, breast cancer cell growth, breast cancer cell‐induced osteolytic bone lesion area, and bone mineral density (BMD). Curcuminoids, but not ZA, inhibited osteoclast formation at doses that did not alter precursor viability, as assessed by osteoclastogenesis assays using murine RAW 264.7 cells. Combined curcuminoids and ZA did not differ from curcuminoids alone in their effects on osteoclast survival/formation. The half maximal inhibitory concentration (IC50) for ZA alone was 4 μM, while the IC50 for curcuminoids plus ZA was 6μM. Curcuminoids and ZA inhibit in vitro cell viability of human breast cancer‐ derived MDA‐MB‐231 cells, as assessed by MTT assays. The IC50 of ZA alone was projected to be 1.0677 x 10^4 μM, while the IC50 for curcuminoids alone (9.1 x 10^1 μM), was close to the IC50 for curcuminoids plus ZA (1.31 x 10^2 μM curcuminoids with 300 μM ZA). In vivo effects of ZA (2 μg/kg/d) and curcuminoids (25 mg/kg/d), alone and combined, on osteolytic bone lesions dervied from innoculation with MDA‐MB‐231 cells were assessed. Radiographically‐evident osteolytic bone lesion area did not differ between treatment groups, with a trend towards decreased osteolytic lesion area in mice treated with ZA. BMD In non‐responders, without bone or pericardiac tumors, assessed by dual energy x‐ray absorptiometry, was increased in mice administered ZA. Thus, for the first time, the combined in vitro effects of ZA and curcuminoids on osteclast formation and survival were demonstrated, as well as the combined effects of ZA and curcuminoids on bresat cancer‐derived osteolytic bone lesions and BMD. Table of Contents Introduction/Significance ........................................................................................................ 1 Background ............................................................................................................................... 1 Impact ..................................................................................................................................... 17 Aims/Goals/Hypotheses ......................................................................................................... 20 Research Materials and Methods ................................................................................................ 22 Results ........................................................................................................................................... 27 Discussion ..................................................................................................................................... 56 Future Directions .......................................................................................................................... 61 Conclusions ................................................................................................................................... 62 References .................................................................................................................................... 63 List of Figures and Tables INTRODUCTION/SIGNIFICANCE and RESEARCH MATERIALS AND METHODS Figure 1: The essential steps in the process of tumor cell metastasis to bone. Figure 2: Turmeric is obtained from the roots of the plant Curcuma longa. Figure 3: Bone mineral density was determined in anesthetized mice at day 20 post‐intracardiac injection using a PIXImus densitometer. RESULTS Figure 1: Zoledronic acid and cucruminoids inhibit in vitro cell viability of MDA‐MB‐231 cells, with differential effects when used in combination. Figure 2: Zoledronic acid and curcuminoids dose‐dependently inhibit the viability of RAW 264.7 cells. Figure 3: Curcuminoids, but not zoledronic acid, inhibit osteoclast formation at doses that do not alter precursor viability. Figure 4: Combined curcuminoids and zoledronic acid differ from zoledronic acid alone in their effects on osteoclast survival/formation. Table 1: Assessment of treatment toxicity. Figure 5: Zoledronic acid alone increases bone mineral density. Figure 6: Responders demonstrated no differences in body weights throughout treatment. Table 2: Incidence of radiographically‐evident osteolytic bone lesions. Figure 7: Radiographically‐evident osteolytic bone lesion area did not differ between treatment groups. Figure 8: Representative micrographs of osteolytic bone lesions. INTRODUCTION/SIGNIFICANCE BACKGROUND Breast Cancer Bone Metastases – Clinical Perspective At initial clinical presentation, 5% of all breast cancer patients exhibit primary distant metastases. Metastatic breast cancer is considered incurable (Ruiterkamp et al. 2011). In patients with secondary metastatic breast cancer, defined as recurrence by distant metastases, sites of metastases are bone (85%), liver (40‐50%), pleuritis carcinomatosa (20%), lung (15‐25%) and brain (6‐16%). For these patients, median survival is 58 months after recurrence, with an overall 5‐year survival of 44% (Ruiterkamp et al. 2011). Metastasis to distant sites is the main cause of mortality in breast cancer patients (Weigelt et al 2005). At autopsy, approximately 70% of patients who die from breast cancer exhibit evidence of metastatic bone disease. These lytic bone lesions are associated with significant morbidity and poor patient prognosis (Coleman 2006). Based on the poor clinical outcome associated with breast cancer metastasis, it is important to develop novel methods that can prevent or ameliorate the metastasis of breast cancer cells. Given the predilection for breast cancer metastasis to bone, it is especially important to develop efficacious methods that can prevent breast cancer metastasis to bone. In the United States, 40% of women diagnosed with breast cancer use natural products (Shen et al. 2002). In a recent article, Dr. Andrew Weil spoke to CNN regarding Steve Jobs’ decision to seek alternative cancer treatments (Weil): “I wish that all cancer patients could partner with integrative oncologists to guide them through the maze of confusing options, avoid fraudulent treatments and scams and make use of all safe and effective therapies to eliminate tumors, prevent recurrences and preserve quality of life.” Barriers to acceptance of alternative and complementary treatment on part of allopathic oncologists is in part due to lack of evidence of efficacy and, perhaps most importantly when considering botanical dietary supplements, absence of harm with respect to interference with standard treatments. Bone Overview The functions of the human skeletal system include structural support, protection of internal organs, reservoir of calcium and phosphate, and source of hematopoietic cells. Osseous tissue comprises living cells, including bone‐forming osteoblasts and bone‐resorbing 1 osteoclasts, embedded in an organic matrix that is mineralized. Bone can be classified as cortical (compact) or trabecular (spongy, cancellous). Cortical bone accounts for approximately 80% of total bone mass and is found primarily in the shafts of long bones. Approximately 70% of cortical bone is mineralized, with cortical bone serving a primarily structural/mechanical function. The outer surface of cortical bone is covered with periosteum; the periosteum comprises an outer fibrous layer composed of collagen fibers and fibroblasts and an inner cambium layer of flattened osteoprogenitor cells that can differentiate into osteoblasts. Endosteum comprises osteoprogenitor cells and connective tissue and lines the inner surface of bone. Thus both the periosteum and endosteum provide precursors for bone‐forming osteoblasts. The bone matrix comprises organic matter such as type I collagen fibers composed of fibril bundles and embedded in a ground substance of proteoglycans and glycoproteins. The bone matrix also comprises inorganic matter of hydroxyapatite,
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