Bisphosphonates: from bone anti-resorptive to anti-cancer drugs

Mohammed Helmy, Faris Shalayel, Saeed Alsareii, Abdulhadi Elbashir, Mohammed Huneif
2017 J Med Oncl Ther   unpublished
Bisphosphonates are structurally stable derivatives of inorganic pyrophosphate (PPi) [1] but are chemically reluctant to enzymatic breakdown [2]. It was suggested that inorganic pyrophosphate might be the bodies own natural "water softener" that normally prohibits soft tissues calcification and organizes mineralization of bones. Hence, it became clear that calcification disorders might be associated with defects in PPi metabolism [3]. Bisphosphonates are analogues to a metabolic byproduct
more » ... nd with 2 phosphate groups connected together by esterification, the so-called pyrophosphate. They have sturdy inhibitory influence on bone resorption. Consequently, they are regarded as efficient drugs against bone resorption in bone disorders like, osteoporosis, Paget's disease, multiple myeloma, cancer-induced hypercalcemia, and bony metastases [4]. Resembling their natural analogue PPi, bisphosphonates have a very high affinity for bone mineral as they bind to hydroxyapatite crystals. Therefore, availability of hydroxyapatite binding sites is crucial in bisphosphonate skeletal retention. Bisphosphonates are discriminatorily commingle places of active bone remodeling, as commonly happens in conditions characterized by accelerated skeletal turnover. That are not retained in the skeleton, are rapidly washed out from the circulation by renal clearance. Additionally, they effectively suppress bone resorption by inhibiting hydroxyapatite breakdown [5]. The bisphosphonates suppress osteoclastic bone resorption through a mechanism that differs from that of other antiresorptive compounds [6,7]. They incorporate with hydroxyapatite binding sites on bony surfaces that succumb active resorption impairing the ability of the osteoclasts to form the ruffled border and to produce the protons necessary for sustained bone resorption [7-9]. Bisphosphonates also reduce osteoclast activity by enhancing osteoclast apoptosis and diminishing osteoclast progenitor development and recruitment [10]. In addition, bisphosphonates interfere Bisphosphonates, analogues of pyrophosphates, are utilized as efficient drugs against bone resorption in bone disorders like, osteoporosis, Paget's disease, multiple myeloma, cancer-induced hypercalcemia, and bony metastases. They suppress osteoclastic bone resorption by incorporating with hydroxyapatite binding sites on bony surfaces that undergo active resorption with due interference with various biochemical processes in bone-resorbing osteoclasts, impairing the ability of the osteoclasts and enhancing osteoclast apoptosis. The clinical utilization of bisphosphonates has dramatically expanded during the past 3 decades or more especially for osteoporosis to diminish the frequency of skeletal-related events in patients with breast cancer and myeloma. Some preclinical studies had reported that bisphosphonates exhibit direct and indirect anticancer activities in patients with early breast cancer or symptomatic multiple myeloma exhibiting disease-free survival and overall survival benefits. Moreover, some epidemiological and clinically applied studies concluded that current use of bisphosphonates in healthy postmenopausal women to manage osteoporosis was correlated with a 30% reduction in the risk of breast and colon cancers and ladies who use bisphosphonates had about one half the risk of getting endometrial cancer compared with those who did not use them. Recently, it was reported that addition of bisphosphonates to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) could enhance the antitumor effect of EGFR-TKIs in patients with EGFR-mutant non-small-cell lung cancer and bone metastasis. Abstract
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