Osteoclast‐targeting small molecules for the treatment of neoplastic bone metastases

Abstract

Osteoclasts are highly specialized cells that resorb bone, and their abnormal activity is implicated in a variety of human bone diseases. In neoplastic bone metastasis, the bone destruction caused by osteoclasts is not only associated with the formation and progression of metastatic lesions, but also could contribute to frequent complications such as severe pain and pathological fractures, which greatly diminish the quality of life of patients. Bisphosphonates, potent antiresorptive drugs, have been shown to have efficacy for treating bone metastases in many types of cancer, and the development of various molecularly targeted agents is currently proceeding. Thus, inhibition of osteoclast function is now established as an important treatment strategy for bony metastases. This review focuses on promising small molecules that disrupt osteoclast function and introduces our chemical ⁄ biological approach for identifying osteoclast-targeting small molecular inhibitors. (Cancer Sci 2009; 100: 1999 B one is a dynamic organ that constantly repeats the cycle of formation by osteoblasts and destruction (resorption) by osteoclasts throughout life.(1) Bone remodeling is necessary for skeletal growth and to maintain normal bone tissue. Imbalances of remodeling can result in gross perturbations in skeletal structure and function, potentially causing morbidity. Most adult skeletal diseases are due to excess osteoclastic bone resorption, including osteoporosis, rheumatoid arthritis, and neoplastic bone metastasis.(2) Bone, as well as lung and liver, is one of the most preferential metastatic sites for common human malignancies, notably breast, prostate, and lung cancers.(3) Bone metastases are frequently associated with severe bone pain, pathological fractures, hypercalcemia, and spinal cord compression syndromes that greatly diminish the quality of life for patients. Although bone metastases are histopathologically classified as osteolytic, osteoblastic, or mixed lesions, accumulating evidence suggests that bone resorption by osteoclasts plays a pivotal role in the development and progression of all types of metastasis.(4) In fact, bone-residing metastatic cells are not directly able to destroy the hard bone tissue to enable them to survive and grow within bone. Instead, they secrete paracrine factors, such as parathyroid hormone-related peptide (PTHrP) and interleukin-6 (IL-6), which directly or indirectly stimulate osteoclast differentiation and activation. In turn, bone resorption by osteoclasts releases growth factors such as transforming growth factor-b (TGF-b) and insulin-like growth factor-1 (IGF-1) from the bone matrix that promote tumor growth. This interaction between tumor cells and the bony microenvironment results in a vicious cycle of bone destruction and tumor growth (Fig. 1).(4) Furthermore, excessive osteoclastic bone destruction could be a factor that causes the complications of metastases.The concept of the vicious cycle alters the approach to the treatment of bone metastases, because it means that antiresorp...

Targeted Therapy Options for Treatment of Bone Metastases; Beyond Bisphosphonates

“…Systemically administered bisphosphonates were the first (FDA-)approved bonetargeted drug therapy for treatment of bone metastases [34]. Bisphosphonates have a high affinity for hydroxy-apatite crystals in mineralized bone where they accumulate and are internalized by osteoclasts, inducing osteoclast apoptosis, thereby inhibiting bone resorption [23,37,55,56].…”

RGD peptide conjugated liposomal drug delivery system for enhance therapeutic efficacy in treating bone metastasis from prostate cancer

“…Bone metastases are predominant in breast (65 − 75%), prostate (65 − 75%), thyroid (60%), lung (30 − 40%), and kidney cancer (20 − 25%) [2]. The patients with bone metastases suffer from high death rate, pain, and decreased quality of life, resulting from osteoclastic and/or osteoblastic bone lesions and its clinically important complications such as fracture, need for radiotherapy and/or chemotherapy, spinal cord compression, or hypercalcemia [3]. Patients who are diagnosed with bone metastases generally cannot be treated curatively in spite of extensive research, e.g., only 46% of patients with prostate cancer, 20% of patients with breast cancer, and less than 10% of patients with lung cancer are still alive five years after the diagnosis of bone metastases [2].…”

“…Recently, several targeted therapeutic agents that inhibit osteoclastmediated bone resorption (Vacuolar H + -ATPase inhibitors, RANKL inhibitor, c-Src Inhibitors, αvβ3 integrin inhibitors, Cathepsin K inhibitors, bisphosphonates, etc) [3,7] and restore osteoblast functions (DKK-1 inhibitors, Activin A inhibitors, etc) [8] have been studied or evaluated in clinical trials. Although these do reduce some degree of metastatic growth, providing symptomatic relief and regression of bone disease, none of them have been proven to significantly control tumor progression or improve overall survival [9].…”

Halenaquinone inhibits RANKL-induced osteoclastogenesis

“…Since the deregulation of osteoclast functions has been associated with several diseases including osteoporosis and bone-metastasis, considerable and widespread attention has been focused on compounds that affect osteoclastogenesis and the functions of osteoclasts for the treatment of osteoclast-related diseases. 4,5 In the present study, we isolated halenaquinone 6 (1) (Fig. 1) from the marine sponge Petrosia alfiani as an inhibitor of osteoclastogenic differentiation of murine RAW264 cells.…”