RESUMEN
We have demonstrated previously that the brassinosteroid (BR) 24-epibrassinolide exerts neuroprotective effects deriving from its antioxidative properties. In this study, we synthesized 2 natural BRs and 5 synthetic analogs and analyzed their neuroprotective actions in neuronal PC12 cells, against 1-methyl-4-phenylpyridinium (MPP(+)), a neurotoxin known to induce oxidative stress and degenerescence of dopaminergic neurons characteristic of Parkinsonian brains. We also tested the neuroprotective potential of 2 commercially available BRs. Our results disclosed that 6 of the 9 BRs and analogs tested protected neuronal PC12 cells against MPP(+) toxicity. In addition, our structure-activity study suggests that the steroid B-ring and lateral chain play an important role for their neuroprotective action.
Asunto(s)
1-Metil-4-fenilpiridinio/efectos adversos , Antioxidantes/síntesis química , Brasinoesteroides/síntesis química , Neuronas Dopaminérgicas/efectos de los fármacos , Fármacos Neuroprotectores/síntesis química , Enfermedad de Parkinson/prevención & control , Animales , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Brasinoesteroides/farmacología , Brasinoesteroides/uso terapéutico , Neuronas Dopaminérgicas/citología , Neuronas Dopaminérgicas/metabolismo , Humanos , Estructura Molecular , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Estrés Oxidativo , Células PC12 , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Ratas , Relación Estructura-ActividadRESUMEN
PURPOSE OF REVIEW: Cancer cells that metastasize to the skeleton are, on their own, rarely able to destroy bone. Instead, they stimulate the function of bone-degrading cells, the osteoclasts, leading to the formation of osteolytic lesions. The purpose of this review is to consider cathepsin K, a cysteine protease produced by osteoclasts, as a therapeutic target for the treatment of patients with osteolytic bone metastases. RECENT FINDINGS: Cathepsin K plays a key role in osteoclast-mediated bone degradation. It is also produced by cancer cells that metastasize to bone where it functions in proteolytic pathways that promote cancer cell invasion. Highly selective and potent cathepsin K inhibitors have been recently developed and shown to be useful antiresorptive agents to treat osteoporosis. Moreover, preclinical studies show that cathepsin K inhibitors reduce breast cancer-induced osteolysis and skeletal tumor burden. This reduction of skeletal tumor burden is due to the antiresorptive activity of cathepsin K inhibitors, which in turn, deprive cancer cells of bone-derived growth factors that are required for tumor growth. SUMMARY: Cathepsin K inhibitors are appropriate drugs to treat diseases associated with increased bone loss. However, their chronic use in treating osteoporosis may result in adverse effects because basic nitrogen-containing cathepsin K inhibitors accumulate within acidic organelles such as lysosomes, thereby inhibiting the activity of other cathepsins. These adverse effects should not, however, preclude the use of these drugs in life-threatening diseases such as bone metastasis.
Asunto(s)
Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/secundario , Catepsinas/antagonistas & inhibidores , Azepinas/uso terapéutico , Benzamidas/uso terapéutico , Compuestos de Bifenilo/uso terapéutico , Neoplasias Óseas/metabolismo , Remodelación Ósea , Resorción Ósea/metabolismo , Resorción Ósea/patología , Neoplasias de la Mama/patología , Catepsina K , Femenino , Humanos , Masculino , Osteoclastos/metabolismo , Osteoclastos/patología , Piperazinas/uso terapéutico , Neoplasias de la Próstata/patología , Sulfonas/uso terapéutico , Tiazoles/uso terapéuticoRESUMEN
Osteoclasts mediate bone destruction in breast cancer skeletal metastases. Cathepsin K is a proteinase that is secreted by osteoclasts and degrades bone. Here, immunohistochemistry revealed that cathepsin K was expressed not only by osteoclasts but also by breast cancer cells that metastasize to bone. Following intratibial injection with cathepsin K-expressing human BT474 breast cancer cells, tumor-bearing mice treated with a clinical dosing regimen of cathepsin K inhibitor (CKI; 50 mg/kg, twice daily) had osteolytic lesions that were 79% smaller than those of tumor-bearing mice treated with the vehicle. The effect of CKI was also studied in a mouse model in which the i.v. inoculation of human B02 breast cancer cells expressing cathepsin K leads to bone metastasis formation. Drug administration was started before (preventive protocol) or after (treatment protocol) the occurrence of osteolytic lesions. In treatment protocols, CKI (50 mg/kg, twice daily) or a single clinical dose of 100 microg/kg zoledronic acid (osteoclast inhibitor) reduced the progression of osteolytic lesions by 59% to 66%. CKI therapy also reduced skeletal tumor burden by 62% compared with vehicle, whereas zoledronic acid did not decrease the tumor burden. The efficacy of CKI at inhibiting skeletal tumor burden was similar in the treatment and preventive protocols. By contrast, CKI did not block the growth of s.c. B02 tumor xenografts in animals. Thus, CKI may render the bone a less favorable microenvironment for tumor growth by inhibiting bone resorption. These findings raise the possibility that cathepsin K could be a therapeutic target for the treatment of bone metastases.
Asunto(s)
Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/secundario , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/enzimología , Catepsinas/antagonistas & inhibidores , Inhibidores de Cisteína Proteinasa/farmacología , Animales , Neoplasias Óseas/enzimología , Neoplasias Óseas/prevención & control , Neoplasias de la Mama/patología , Catepsina K , Catepsinas/biosíntesis , Línea Celular Tumoral , Humanos , Inmunohistoquímica , Ratones , Ratones Desnudos , Osteólisis/tratamiento farmacológico , Osteólisis/enzimología , Osteólisis/prevención & control , Distribución Aleatoria , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Bisphosphonates exhibit direct antitumor activity in animal models, but only at high doses that are incompatible with the clinical dosing regimens approved for the treatment of cancer patients with skeletal metastases. We compared the antitumor effects of clinical dosing regimens of the bisphosphonates zoledronic acid and clodronate in a mouse model of bone metastasis. METHODS: Mice (n = 6-10 per group) were treated with zoledronic acid, clodronate, or vehicle starting before (preventive protocols) or after (treatment protocols) intravenous injection with human B02/GFP.2 breast cancer cells, which express green fluorescent protein (GFP) and luciferase and metastasize to bone. Zoledronic acid was given as daily, weekly, or single doses at a cumulative dose of 98-100 microg/kg body weight, equivalent to the 4-mg intravenous dose given to patients. Clodronate was given as a daily dose (530 microg/kg/day), equivalent to the daily 1600-mg oral clinical dose given to patients. Bone destruction was measured by radiography, x-ray absorptiometry or tomography, and histomorphometry (as the ratio of bone volume to tissue volume). Skeletal tumor burden was measured by histomorphometry (as the ratio of tumor burden to soft tissue volume [TB/STV]) and luciferase activity. All statistical tests were two-sided. RESULTS: In treatment protocols, daily clodronate was less effective at decreasing the TB/STV ratio than daily (53% versus 87%, difference = 34%, 95% confidence interval [CI] = 16% to 44%, P < .001) or weekly (53% versus 90%, difference = 37%, 95% CI = 19% to 46%, P < .001) zoledronic acid-dosing regimens. Compared with vehicle, a single dose of zoledronic acid decreased tumor burden by only 16% (95% CI = 9% to 22%, P < .001). In preventive protocols, daily clodronate and daily or weekly zoledronic acid decreased the TB/STV ratio by 49% (95% CI = 40% to 57%, P = .006), 83% (95% CI = 68% to 98%, P < .001), and 66% (95% CI = 47% to 84%, P < .001), respectively, compared with vehicle, whereas a single dose of zoledronic acid decreased tumor burden by only 13% (95% CI = -2% to 28%, P = .84). Mice treated with a daily preventive regimen of clodronate or with a daily or weekly preventive regimen of zoledronic acid showed a decreased B02/GFP.2 cell tumor burden compared with vehicle, whereas a single preventive dose of zoledronic acid had no effect. CONCLUSION: Daily or repeated intermittent therapy with clinical doses of bisphosphonates inhibits skeletal tumor growth in a mouse model.