39 research outputs found
The effects of enzalutamide and abiraterone on skeletal related events and bone radiological progression free survival in castration resistant prostate cancer patients: An indirect comparison of randomized controlled trials
Two new drugs, the CYP17 inhibitor abiraterone acetate and the androgen receptor (AR) antagonist enzalutamide, have recently shown to prolong OS prior chemotherapy or in docetaxel treated mCRPC patients, using steroidal therapy or placebo as control group. Updated analyses underlined the role of these new agents on two prostate-specific endpoints as radiographic progression-free survival (rPFS) and time to first skeletal-related event (tSRE). On the basis of these reports, we made an indirect comparison between abiraterone and enzalutamide. We obtained a clinically but not significant difference favouring enzalutamide over abiraterone in terms of rPFS (HR 0.48, 95% CI 0.22Γ’1.02). No significant difference was shown in term of tSRE (HR 0.99, 95% CI 0.83Γ’1.17). In conclusion, abiraterone and enzalutamide have both demonstrated to significantly delay the bone progression resulting in similar improvements in bone-related endpoints in patients with mCRPC
Biological and clinical effects of abiraterone on anti-resorptive and anabolic activity in bone microenvironment
Abiraterone acetate (ABI) is associated not only with a significant survival advantage in both chemotherapy-naive and -treated patients with metastatic castration-resistant prostate cancer (mCRPC), but also with a delay in time to development of Skeletal Related Events and in radiological skeletal progression. These bone benefits may be related to a direct effect on prostate cancer cells in bone or to a specific mechanism directed to bone microenvironment. To test this hypothesis we designed an in vitro study aimed to evaluate a potential direct effect of ABI on human primary osteoclasts/osteoblasts (OCLs/OBLs). We also assessed changes in bone turnover markers, serum carboxy-terminal collagen crosslinks (CTX) and alkaline phosphatase (ALP), in 49 mCRPC patients treated with ABI.Our results showed that non-cytotoxic doses of ABI have a statistically significant inhibitory effect on OCL differentiation and activity inducing a down-modulation of OCL marker genes TRAP, cathepsin K and metalloproteinase-9. Furthermore ABI promoted OBL differentiation and bone matrix deposition up-regulating OBL specific genes, ALP and osteocalcin. Finally, we observed a significant decrease of serum CTX values and an increase of ALP in ABI-treated patients.These findings suggest a novel biological mechanism of action of ABI consisting in a direct bone anabolic and anti-resorptive activity
Changes in bone turnover markers in patients without bone metastases receiving immune checkpoint inhibitors: An exploratory analysis
Immune checkpoint inhibitors (ICIs) has revolutionized the treatment of different advanced solid tumors, but most patients develop severe immune-related adverse events (irAEs). Although a bi-directional crosstalk between bone and immune systems is widely described, the effect of ICIs on the skeleton is poorly investigated. Here, we analyze the changes in plasma levels of type I collagen C-terminal telopeptide (CTX-I) and N-terminal propeptide of type I procollagen (PINP), reference makers of bone turnover, in patients treated with ICIs and their associ-ation with clinical outcome.A series of 44 patients affected by advanced non-small cell lung cancer or renal cell carcinoma, without bone metastases, and treated with ICIs as monotherapy were enrolled. CTX-I and PINP plasma levels were assessed at baseline and after 3 months of ICIs treatment by ELISA kits.A significant increase of CTX-I with a concomitant decreasing trend towards the reduction of PINP was observed after 3 months of treatment. Intriguingly, CTX-I increase was associated with poor prognosis in terms of treatment response and survival. These data suggest a direct relationship between ICIs treatment, increased osteoclast activity and potential fracture risk.Overall, this study reveals that ICIs may act as triggers for skeletal events, and if confirmed in larger pro-spective studies, it would identify a new class of skeletal-related irAEs
ΠΠΈΠΎΠ»ΠΎΠ³ΠΈΡΠ΅ΡΠΊΠΎΠ΅ ΠΈ ΠΊΠ»ΠΈΠ½ΠΈΡΠ΅ΡΠΊΠΎΠ΅ Π΄Π΅ΠΉΡΡΠ²ΠΈΠ΅ Π°Π±ΠΈΡΠ°ΡΠ΅ΡΠΎΠ½Π° Π½Π° Π°Π½ΡΠΈΡΠ΅Π·ΠΎΡΠ±ΡΠΈΠ²Π½ΡΡ ΠΈ Π°Π½Π°Π±ΠΎΠ»ΠΈΡΠ΅ΡΠΊΡΡ Π°ΠΊΡΠΈΠ²Π½ΠΎΡΡΡ ΠΌΠΈΠΊΡΠΎΠΎΠΊΡΡΠΆΠ΅Π½ΠΈΡ ΠΊΠΎΡΡΠ½ΠΎΠΉ ΡΠΊΠ°Π½ΠΈ
ΠΡΠΈΠΌΠ΅Π½Π΅Π½ΠΈΠ΅ Π°Π±ΠΈΡΠ°ΡΠ΅ΡΠΎΠ½Π° Π°ΡΠ΅ΡΠ°ΡΠ° (ΠΠ) ΡΠΎΠΏΡΠΎΠ²ΠΎΠΆΠ΄Π°Π΅ΡΡΡ Π½Π΅ ΡΠΎΠ»ΡΠΊΠΎ Π·Π½Π°ΡΠΈΠΌΡΠΌ ΡΠ²Π΅Π»ΠΈΡΠ΅Π½ΠΈΠ΅ΠΌ Π²ΡΠΆΠΈΠ²Π°Π΅ΠΌΠΎΡΡΠΈ ΠΏΠ°ΡΠΈΠ΅Π½ΡΠΎΠ² Ρ ΠΌΠ΅ΡΠ°ΡΡΠ°ΡΠΈΡΠ΅ΡΠΊΠΈΠΌ ΠΊΠ°ΡΡΡΠ°ΡΠΈΠΎΠ½Π½ΠΎ-ΡΠ΅Π·ΠΈΡΡΠ΅Π½ΡΠ½ΡΠΌ ΡΠ°ΠΊΠΎΠΌ ΠΏΡΠ΅Π΄ΡΡΠ°ΡΠ΅Π»ΡΠ½ΠΎΠΉ ΠΆΠ΅Π»Π΅Π·Ρ (ΠΌΠΠ Π ΠΠ), Π½ΠΎ ΡΠ°ΠΊΠΆΠ΅ ΠΎΡΠ΄Π°Π»Π΅Π½ΠΈΠ΅ΠΌ Π²ΡΠ΅ΠΌΠ΅Π½ΠΈ Π΄ΠΎ ΡΠ°Π·Π²ΠΈΡΠΈΡ ΡΠ΅Π½ΡΠ³Π΅Π½ΠΎΠ»ΠΎΠ³ΠΈΡΠ΅ΡΠΊΠΎΠ³ΠΎ ΠΏΡΠΎΠ³ΡΠ΅ΡΡΠΈΡΠΎΠ²Π°Π½ΠΈΡ Π·Π°Π±ΠΎΠ»Π΅Π²Π°Π½ΠΈΡ. ΠΡΠΈ ΠΏΡΠ΅ΠΈΠΌΡΡΠ΅ΡΡΠ²Π° ΠΎΡΠ½ΠΎΡΠΈΡΠ΅Π»ΡΠ½ΠΎ ΠΊΠΎΡΡΠ½ΡΡ
ΠΌΠ΅ΡΠ°ΡΡΠ°ΡΠΈΡΠ΅ΡΠΊΠΈΡ
ΠΎΡΠ°Π³ΠΎΠ² ΠΌΠΎΠ³ΡΡ Π±ΡΡΡ ΡΠ²ΡΠ·Π°Π½Ρ Ρ Π½Π΅ΠΏΠΎΡΡΠ΅Π΄ΡΡΠ²Π΅Π½Π½ΡΠΌ Π²ΠΎΠ·Π΄Π΅ΠΉΡΡΠ²ΠΈΠ΅ΠΌ Π½Π° ΠΌΠ΅ΡΠ°ΡΡΠ°ΡΠΈΡΠ΅ΡΠΊΠΈΠ΅ ΠΊΠ»Π΅ΡΠΊΠΈ ΡΠ°ΠΊΠ° ΠΏΡΠ΅Π΄ΡΡΠ°ΡΠ΅Π»ΡΠ½ΠΎΠΉ ΠΆΠ΅Π»Π΅Π·Ρ Π² ΠΊΠΎΡΡΡΡ
ΠΈΠ»ΠΈ ΡΠΎ ΡΠΏΠ΅ΡΠΈΡΠΈΡΠ΅ΡΠΊΠΈΠΌΠΈ ΠΌΠ΅Ρ
Π°Π½ΠΈΠ·ΠΌΠ°ΠΌΠΈ, Π½Π°ΠΏΡΠ°Π²Π»Π΅Π½Π½ΡΠΌΠΈ Π½Π° ΠΊΠΎΡΡΠ½ΠΎΠ΅ ΠΌΠΈΠΊΡΠΎΠΎΠΊΡΡΠΆΠ΅Π½ΠΈΠ΅. Π§ΡΠΎΠ±Ρ ΠΏΡΠΎΠ²Π΅ΡΠΈΡΡ ΡΡΠΈ Π³ΠΈΠΏΠΎΡΠ΅Π·Ρ, ΠΌΡ ΠΏΡΠΎΠ²Π΅- Π»ΠΈ ΠΈΡΡΠ»Π΅Π΄ΠΎΠ²Π°Π½ΠΈΠ΅ in vitro, Π½Π°ΠΏΡΠ°Π²Π»Π΅Π½Π½ΠΎΠ΅ Π½Π° ΠΎΡΠ΅Π½ΠΊΡ ΠΏΠΎΡΠ΅Π½ΡΠΈΠ°Π»ΡΠ½ΠΎΠ³ΠΎ Π΄Π΅ΠΉΡΡΠ²ΠΈΡ AA Π½Π° ΠΏΠ΅ΡΠ²ΠΈΡΠ½ΡΠ΅ ΠΎΡΡΠ΅ΠΎΠΊΠ»Π°ΡΡΡ (ΠΠΠ) / ΠΎΡΡΠ΅ΠΎΠ±Π»Π°ΡΡΡ (ΠΠΠ); in vivo ΠΎΡΠ΅Π½ΠΈΠ²Π°Π»ΠΈ ΠΈΠ·ΠΌΠ΅Π½Π΅Π½ΠΈΡ ΡΡΠΎΠ²Π½Π΅ΠΉ ΠΌΠ°ΡΠΊΠ΅ΡΠΎΠ² ΠΊΠΎΡΡΠ½ΠΎΠ³ΠΎ ΠΌΠ΅ΡΠ°Π±ΠΎΠ»ΠΈΠ·ΠΌΠ°, Π‘-ΠΊΠΎΠ½ΡΠ΅Π²ΡΡ
ΡΠ΅Π»ΠΎΠΏΠ΅ΠΏΡΠΈΠ΄ΠΎΠ² ΠΊΠΎΠ»Π»Π°Π³Π΅Π½Π° 1-Π³ΠΎ ΡΠΈΠΏΠ° (CTX, ΠΌΠ°ΡΠΊΠ΅Ρ ΠΊΠΎΡΡΠ½ΠΎΠΉ ΡΠ΅Π·ΠΎΡΠ±ΡΠΈΠΈ) ΠΈ ΡΠ΅Π»ΠΎΡΠ½ΠΎΠΉ ΡΠΎΡΡΠ°ΡΠ°Π·Ρ (Π©Π€) Ρ 49 ΠΏΠ°ΡΠΈΠ΅Π½ΡΠΎΠ² Ρ ΠΌΠΠ Π ΠΠ, ΠΏΠΎΠ»ΡΡΠ°Π²ΡΠΈΡ
AA.ΠΠ°ΡΠΈ ΡΠ΅Π·ΡΠ»ΡΡΠ°ΡΡ ΠΏΠΎΠΊΠ°Π·Π°Π»ΠΈ, ΡΡΠΎ AA ΠΎΠΊΠ°Π·ΡΠ²Π°Π΅Ρ ΡΡΠ°ΡΠΈΡΡΠΈΡΠ΅ΡΠΊΠΈ Π·Π½Π°ΡΠΈΠΌΠΎΠ΅ ΠΈΠ½Π³ΠΈΠ±ΠΈΡΡΡΡΠ΅Π΅ Π΄Π΅ΠΉΡΡΠ²ΠΈΠ΅ Π½Π° Π΄ΠΈΡΡΠ΅ΡΠ΅Π½ΡΠΈΡΠΎΠ²ΠΊΡ ΠΈ Π°ΠΊΡΠΈΠ²Π½ΠΎΡΡΡ ΠΠΠ, ΡΠΌΠ΅Π½ΡΡΠ°Ρ ΡΠΊΡΠΏΡΠ΅ΡΡΠΈΡ ΠΠΠ-ΠΌΠ°ΡΠΊΠ΅ΡΠ½ΡΡ
Π³Π΅Π½ΠΎΠ² TRAP (ΡΠ°ΡΡΡΠ°ΡΡΠ΅Π·ΠΈΡΡΠ΅Π½ΡΠ½Π°Ρ ΠΊΠΈΡΠ»Π°Ρ ΡΠΎΡΡΠ°ΡΠ°Π·Π°), ΠΎΠ±ΡΠ°Π·ΠΎΠ²Π°Π½ΠΈΠ΅ ΠΊΠ°ΡΠ΅ΠΏΡΠΈΠ½Π° Π ΠΈ ΠΌΠ°ΡΡΠΈΠΊΡΠ½ΠΎΠΉ ΠΌΠ΅ΡΠ°Π»Π»ΠΎΠΏΡΠΎΡΠ΅ΠΈΠ½Π°Π·Ρ-9. ΠΡΠΎΠΌΠ΅ ΡΠΎΠ³ΠΎ, AA ΡΠΏΠΎΡΠΎΠ±ΡΡΠ²ΠΎΠ²Π°Π» Π΄ΠΈΡΡΠ΅ΡΠ΅Π½ΡΠΈΡΠΎΠ²ΠΊΠ΅ ΠΠΠ ΠΈ ΠΎΡΠ»ΠΎΠΆΠ΅Π½ΠΈΡ ΠΊΠΎΡΡΠ½ΠΎΠΉ ΠΌΠ°ΡΡΠΈΡΡ, ΡΠ²Π΅Π»ΠΈΡΠΈΠ²Π°Ρ ΡΠΊΡΠΏΡΠ΅ΡΡΠΈΡ ΡΠΏΠ΅ΡΠΈΡΠΈΡΠ½ΡΡ
Π΄Π»Ρ ΠΠΠ Π³Π΅Π½ΠΎΠ² RUNX2 (ΡΠ°ΠΊΡΠΎΡ ΡΡΠ°Π½ΡΠΊΡΠΈΠΏΡΠΈΠΈ-2, ΡΠΎΠ΄Π΅ΡΠΆΠ°ΡΠΈΠΉ Π΄ΠΎΠΌΠ΅Π½ Runt), ΠΎΠ±ΡΠ°Π·ΠΎΠ²Π°Π½ΠΈΠ΅ Π©Π€ ΠΈ ΠΎΡΡΠ΅ΠΎΠΊΠ°Π»ΡΡΠΈΠ½Π°. Π’Π°ΠΊΠΆΠ΅ ΠΌΡ Π½Π°Π±Π»ΡΠ΄Π°Π»ΠΈ in vivo Π·Π½Π°ΡΠΈΠΌΠΎΠ΅ ΡΠ½ΠΈΠΆΠ΅Π½ΠΈΠ΅ ΡΡΠΎΠ²Π½Ρ CTX Π² ΡΡΠ²ΠΎΡΠΎΡΠΊΠ΅ ΠΈ ΠΏΠΎΠ²ΡΡΠ΅Π½ΠΈΠ΅ ΡΡΠΎΠ²Π½Ρ Π©Π€ Ρ ΠΏΠ°ΡΠΈΠ΅Π½ΡΠΎΠ², ΠΏΠΎΠ»ΡΡΠ°Π²ΡΠΈΡ
AA.ΠΡΠΈ Π΄Π°Π½Π½ΡΠ΅ ΠΏΠΎΠ·Π²ΠΎΠ»ΡΡΡ ΠΏΡΠ΅Π΄ΠΏΠΎΠ»Π°Π³Π°ΡΡ Π½ΠΎΠ²ΡΠΉ Π±ΠΈΠΎΠ»ΠΎΠ³ΠΈΡΠ΅ΡΠΊΠΈΠΉ ΠΌΠ΅Ρ
Π°Π½ΠΈΠ·ΠΌ Π΄Π΅ΠΉΡΡΠ²ΠΈΡ AA, ΡΠΎΡΡΠΎΡΡΠΈΠΉ Π² ΠΏΡΡΠΌΠΎΠΌ Π°Π½Π°Π±ΠΎΠ»ΠΈΡΠ΅ΡΠΊΠΎΠΌ ΠΈ Π°Π½ΡΠΈΡΠ΅Π·ΠΎΡΠ±ΡΠΈΠ²Π½ΠΎΠΌ Π²Π»ΠΈΡΠ½ΠΈΠΈ Π½Π° ΠΊΠΎΡΡΠ½ΡΡ ΡΠΊΠ°Π½Ρ.ΠΡΠΈΠΌΠ΅Π½Π΅Π½ΠΈΠ΅ Π°Π±ΠΈΡΠ°ΡΠ΅ΡΠΎΠ½Π° Π°ΡΠ΅ΡΠ°ΡΠ° (ΠΠ) ΡΠΎΠΏΡΠΎΠ²ΠΎΠΆΠ΄Π°Π΅ΡΡΡ Π½Π΅ ΡΠΎΠ»ΡΠΊΠΎ Π·Π½Π°ΡΠΈΠΌΡΠΌ ΡΠ²Π΅Π»ΠΈΡΠ΅Π½ΠΈΠ΅ΠΌ Π²ΡΠΆΠΈΠ²Π°Π΅ΠΌΠΎΡΡΠΈ ΠΏΠ°ΡΠΈΠ΅Π½ΡΠΎΠ² Ρ ΠΌΠ΅ΡΠ°ΡΡΠ°ΡΠΈΡΠ΅ΡΠΊΠΈΠΌ ΠΊΠ°ΡΡΡΠ°ΡΠΈΠΎΠ½Π½ΠΎ-ΡΠ΅Π·ΠΈΡΡΠ΅Π½ΡΠ½ΡΠΌ ΡΠ°ΠΊΠΎΠΌ ΠΏΡΠ΅Π΄ΡΡΠ°ΡΠ΅Π»ΡΠ½ΠΎΠΉ ΠΆΠ΅Π»Π΅Π·Ρ (ΠΌΠΠ Π ΠΠ), Π½ΠΎ ΡΠ°ΠΊΠΆΠ΅ ΠΎΡΠ΄Π°Π»Π΅Π½ΠΈΠ΅ΠΌ Π²ΡΠ΅ΠΌΠ΅Π½ΠΈ Π΄ΠΎ ΡΠ°Π·Π²ΠΈΡΠΈΡ ΡΠ΅Π½ΡΠ³Π΅Π½ΠΎΠ»ΠΎΠ³ΠΈΡΠ΅ΡΠΊΠΎΠ³ΠΎ ΠΏΡΠΎΠ³ΡΠ΅ΡΡΠΈΡΠΎΠ²Π°Π½ΠΈΡ Π·Π°Π±ΠΎΠ»Π΅Π²Π°Π½ΠΈΡ. ΠΡΠΈ ΠΏΡΠ΅ΠΈΠΌΡΡΠ΅ΡΡΠ²Π° ΠΎΡΠ½ΠΎΡΠΈΡΠ΅Π»ΡΠ½ΠΎ ΠΊΠΎΡΡΠ½ΡΡ
ΠΌΠ΅ΡΠ°ΡΡΠ°ΡΠΈΡΠ΅ΡΠΊΠΈΡ
ΠΎΡΠ°Π³ΠΎΠ² ΠΌΠΎΠ³ΡΡ Π±ΡΡΡ ΡΠ²ΡΠ·Π°Π½Ρ Ρ Π½Π΅ΠΏΠΎΡΡΠ΅Π΄ΡΡΠ²Π΅Π½Π½ΡΠΌ Π²ΠΎΠ·Π΄Π΅ΠΉΡΡΠ²ΠΈΠ΅ΠΌ Π½Π° ΠΌΠ΅ΡΠ°ΡΡΠ°ΡΠΈΡΠ΅ΡΠΊΠΈΠ΅ ΠΊΠ»Π΅ΡΠΊΠΈ ΡΠ°ΠΊΠ° ΠΏΡΠ΅Π΄ΡΡΠ°ΡΠ΅Π»ΡΠ½ΠΎΠΉ ΠΆΠ΅Π»Π΅Π·Ρ Π² ΠΊΠΎΡΡΡΡ
ΠΈΠ»ΠΈ ΡΠΎ ΡΠΏΠ΅ΡΠΈΡΠΈΡΠ΅ΡΠΊΠΈΠΌΠΈ ΠΌΠ΅Ρ
Π°Π½ΠΈΠ·ΠΌΠ°ΠΌΠΈ, Π½Π°ΠΏΡΠ°Π²Π»Π΅Π½Π½ΡΠΌΠΈ Π½Π° ΠΊΠΎΡΡΠ½ΠΎΠ΅ ΠΌΠΈΠΊΡΠΎΠΎΠΊΡΡΠΆΠ΅Π½ΠΈΠ΅. Π§ΡΠΎΠ±Ρ ΠΏΡΠΎΠ²Π΅ΡΠΈΡΡ ΡΡΠΈ Π³ΠΈΠΏΠΎΡΠ΅Π·Ρ, ΠΌΡ ΠΏΡΠΎΠ²Π΅Π»ΠΈ ΠΈΡΡΠ»Π΅Π΄ΠΎΠ²Π°Π½ΠΈΠ΅ in vitro, Π½Π°ΠΏΡΠ°Π²Π»Π΅Π½Π½ΠΎΠ΅ Π½Π° ΠΎΡΠ΅Π½ΠΊΡ ΠΏΠΎΡΠ΅Π½ΡΠΈΠ°Π»ΡΠ½ΠΎΠ³ΠΎ Π΄Π΅ΠΉΡΡΠ²ΠΈΡ AA Π½Π° ΠΏΠ΅ΡΠ²ΠΈΡΠ½ΡΠ΅ ΠΎΡΡΠ΅ΠΎΠΊΠ»Π°ΡΡΡ (ΠΠΠ) / ΠΎΡΡΠ΅ΠΎΠ±Π»Π°ΡΡΡ (ΠΠΠ); in vivo ΠΎΡΠ΅Π½ΠΈΠ²Π°Π»ΠΈ ΠΈΠ·ΠΌΠ΅Π½Π΅Π½ΠΈΡ ΡΡΠΎΠ²Π½Π΅ΠΉ ΠΌΠ°ΡΠΊΠ΅ΡΠΎΠ² ΠΊΠΎΡΡΠ½ΠΎΠ³ΠΎ ΠΌΠ΅ΡΠ°Π±ΠΎΠ»ΠΈΠ·ΠΌΠ°, Π‘-ΠΊΠΎΠ½ΡΠ΅Π²ΡΡ
ΡΠ΅Π»ΠΎΠΏΠ΅ΠΏΡΠΈΠ΄ΠΎΠ² ΠΊΠΎΠ»Π»Π°Π³Π΅Π½Π° 1-Π³ΠΎ ΡΠΈΠΏΠ° (CTX, ΠΌΠ°ΡΠΊΠ΅Ρ ΠΊΠΎΡΡΠ½ΠΎΠΉ ΡΠ΅Π·ΠΎΡΠ±ΡΠΈΠΈ) ΠΈ ΡΠ΅Π»ΠΎΡΠ½ΠΎΠΉ ΡΠΎΡΡΠ°ΡΠ°Π·Ρ (Π©Π€) Ρ 49 ΠΏΠ°ΡΠΈΠ΅Π½ΡΠΎΠ² Ρ ΠΌΠΠ Π ΠΠ, ΠΏΠΎΠ»ΡΡΠ°Π²ΡΠΈΡ
AA.ΠΠ°ΡΠΈ ΡΠ΅Π·ΡΠ»ΡΡΠ°ΡΡ ΠΏΠΎΠΊΠ°Π·Π°Π»ΠΈ, ΡΡΠΎ AA ΠΎΠΊΠ°Π·ΡΠ²Π°Π΅Ρ ΡΡΠ°ΡΠΈΡΡΠΈΡΠ΅ΡΠΊΠΈ Π·Π½Π°ΡΠΈΠΌΠΎΠ΅ ΠΈΠ½Π³ΠΈΠ±ΠΈΡΡΡΡΠ΅Π΅ Π΄Π΅ΠΉΡΡΠ²ΠΈΠ΅ Π½Π° Π΄ΠΈΡΡΠ΅ΡΠ΅Π½ΡΠΈΡΠΎΠ²ΠΊΡ ΠΈ Π°ΠΊΡΠΈΠ²Π½ΠΎΡΡΡ ΠΠΠ, ΡΠΌΠ΅Π½ΡΡΠ°Ρ ΡΠΊΡΠΏΡΠ΅ΡΡΠΈΡ ΠΠΠ-ΠΌΠ°ΡΠΊΠ΅ΡΠ½ΡΡ
Π³Π΅Π½ΠΎΠ² TRAP (ΡΠ°ΡΡΡΠ°ΡΡΠ΅Π·ΠΈΡΡΠ΅Π½ΡΠ½Π°Ρ ΠΊΠΈΡΠ»Π°Ρ ΡΠΎΡΡΠ°ΡΠ°Π·Π°), ΠΎΠ±ΡΠ°Π·ΠΎΠ²Π°Π½ΠΈΠ΅ ΠΊΠ°ΡΠ΅ΠΏΡΠΈΠ½Π° Π ΠΈ ΠΌΠ°ΡΡΠΈΠΊΡΠ½ΠΎΠΉ ΠΌΠ΅ΡΠ°Π»Π»ΠΎΠΏΡΠΎΡΠ΅ΠΈΠ½Π°Π·Ρ-9. ΠΡΠΎΠΌΠ΅ ΡΠΎΠ³ΠΎ, AA ΡΠΏΠΎΡΠΎΠ±ΡΡΠ²ΠΎΠ²Π°Π» Π΄ΠΈΡΡΠ΅ΡΠ΅Π½ΡΠΈΡΠΎΠ²ΠΊΠ΅ ΠΠΠ ΠΈ ΠΎΡΠ»ΠΎΠΆΠ΅Π½ΠΈΡ ΠΊΠΎΡΡΠ½ΠΎΠΉ ΠΌΠ°ΡΡΠΈΡΡ, ΡΠ²Π΅Π»ΠΈΡΠΈΠ²Π°Ρ ΡΠΊΡΠΏΡΠ΅ΡΡΠΈΡ ΡΠΏΠ΅ΡΠΈΡΠΈΡΠ½ΡΡ
Π΄Π»Ρ ΠΠΠ Π³Π΅Π½ΠΎΠ² RUNX2 (ΡΠ°ΠΊΡΠΎΡ ΡΡΠ°Π½ΡΠΊΡΠΈΠΏΡΠΈΠΈ-2, ΡΠΎΠ΄Π΅ΡΠΆΠ°ΡΠΈΠΉ Π΄ΠΎΠΌΠ΅Π½ Runt), ΠΎΠ±ΡΠ°Π·ΠΎΠ²Π°Π½ΠΈΠ΅ Π©Π€ ΠΈ ΠΎΡΡΠ΅ΠΎΠΊΠ°Π»ΡΡΠΈΠ½Π°. Π’Π°ΠΊΠΆΠ΅ ΠΌΡ Π½Π°Π±Π»ΡΠ΄Π°Π»ΠΈ in vivo Π·Π½Π°ΡΠΈΠΌΠΎΠ΅ ΡΠ½ΠΈΠΆΠ΅Π½ΠΈΠ΅ ΡΡΠΎΠ²Π½Ρ CTX Π² ΡΡΠ²ΠΎΡΠΎΡΠΊΠ΅ ΠΈ ΠΏΠΎΠ²ΡΡΠ΅Π½ΠΈΠ΅ ΡΡΠΎΠ²Π½Ρ Π©Π€ Ρ ΠΏΠ°ΡΠΈΠ΅Π½ΡΠΎΠ², ΠΏΠΎΠ»ΡΡΠ°Π²ΡΠΈΡ
AA.ΠΡΠΈ Π΄Π°Π½Π½ΡΠ΅ ΠΏΠΎΠ·Π²ΠΎΠ»ΡΡΡ ΠΏΡΠ΅Π΄ΠΏΠΎΠ»Π°Π³Π°ΡΡ Π½ΠΎΠ²ΡΠΉ Π±ΠΈΠΎΠ»ΠΎΠ³ΠΈΡΠ΅ΡΠΊΠΈΠΉ ΠΌΠ΅Ρ
Π°Π½ΠΈΠ·ΠΌ Π΄Π΅ΠΉΡΡΠ²ΠΈΡ AA, ΡΠΎΡΡΠΎΡΡΠΈΠΉ Π² ΠΏΡΡΠΌΠΎΠΌ Π°Π½Π°Π±ΠΎΠ»ΠΈΡΠ΅ΡΠΊΠΎΠΌ ΠΈ Π°Π½ΡΠΈΡΠ΅Π·ΠΎΡΠ±ΡΠΈΠ²Π½ΠΎΠΌ Π²Π»ΠΈΡΠ½ΠΈΠΈ Π½Π° ΠΊΠΎΡΡΠ½ΡΡ ΡΠΊΠ°Π½Ρ
Cabozantinib targets bone microenvironment modulating human osteoclast and osteoblast functions
Cabozantinib, a c-MET and vascular endothelial growth factor receptor 2 inhibitor, demonstrated to prolong progression free survival and improve skeletal diseaserelated endpoints in castration-resistant prostate cancer and in metastatic renal carcinoma. Our purpose is to investigate the direct effect of cabozantinib on bone microenvironment using a total human model of primary osteoclasts and osteoblasts. Osteoclasts were differentiated from monocytes isolated from healthy donors; osteoblasts were derived from human mesenchymal stem cells obtained from bone fragments of orthopedic surgery patients. Osteoclast activity was evaluated by tartrate resistant acid phosphatase (TRAP) staining and bone resorption assays and osteoblast differentiation was detected by alkaline phosphatase and alizarin red staining. Our results show that non-cytotoxic doses of cabozantinib significantly inhibit osteoclast differentiation (p=0.0145) and bone resorption activity (p=0.0252). Moreover, cabozantinib down-modulates the expression of osteoclast marker genes, TRAP (p=0.006), CATHEPSIN K (p=0.004) and Receptor Activator of Nuclear Factor k B (RANK) (p=0.001). Cabozantinib treatment has no effect on osteoblast viability or differentiation, but increases osteoprotegerin mRNA (p=0.015) and protein levels (p=0.004) and down-modulates Receptor Activator of Nuclear Factor k B Ligand (RANKL) at both mRNA (p < 0.001) and protein levels (p=0.043). Direct cell-to-cell contact between cabozantinib pre-treated osteoblasts and untreated osteoclasts confirmed the indirect anti-resorptive effect of cabozantinib. We demonstrate that cabozantinib inhibits osteoclast functions "directly" and "indirectly" reducing the RANKL/osteoprotegerin ratio in osteoblasts