西地那非与他莫昔芬更配

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一、他莫昔芬也是一种有效的 Hsp90 激活剂
他莫昔芬是一种口服活性选择性雌激素受体调节剂 (SERM)，具有雌激素激动剂和拮抗剂作用。它可以阻断乳腺细胞中的雌激素作用，并可以激活其他细胞（例如骨、肝和子宫细胞）中的雌激素活性。
他莫昔芬一般用于绝经前 HR阳性乳腺癌患者。
但他莫昔芬也是一种有效的 Hsp90 激活剂，可增强 Hsp90 分子伴侣 ATPase的活性。
《Tamoxifen Enhances the Hsp90 Molecular Chaperone ATPase Activity》
Methodology/Principal Findings
Using a virtual screening approach, 4-hydroxytamoxifen, the active metabolite of the anti-estrogen drug tamoxifen, was identified as a putative Hsp90 ligand. Surprisingly, while all drugs targeting Hsp90 inhibit the chaperone ATPase activity, it was found experimentally that 4-hydroxytamoxifen and tamoxifen enhance rather than inhibit Hsp90 ATPase.
Conclusions/Significance
Hence, tamoxifen and its metabolite are the first members of a new pharmacological class of Hsp90 activators.

二、hsp90表达高，乳腺癌患者生存率低
《The Prognostic Significance of Hsp70/Hsp90 Expression in Breast Cancer: A Systematic Review and Meta-analysis》
Relevant studies were sought in PubMed, up to December 31, 2015. Results: A total of 23 eligible studies were identified (7,288 breast cancer cases). High Hsp90 expre s sion was associated with worse overall survival (pooled RR=1.48, 95%CI=1.21-1.82) and marginally with worse disease-free survival.

三、西地那非抑制hsp90
1、《Sildenafil triggers tumor lethality through altered expression of HSP90 and degradation of PKD2 》
Notably, incubation of cancer cells with Sildenafil was associated with altered expression of HSP90 chaperone followed by degradation of protein kinase D2, a client protein previously reported to be involved in tumor growth.
2、《PDE5 inhibitors enhance the lethality of [pemetrexed + sorafenib]》
sildenafil to also inactivate the chaperones HSP90 and HSP70 which in turn lost their ability to associate with another chaperone HSP27.
3、《Nexavar/Stivarga and viagra interact to kill tumor cells》
Sildenafil increased the nitration of HSP90, indicative of reduced HSP90 chaperone function
4、《Sildenafil inhibits the growth of human colorectal cancer in vitro and in vivo》
After treatment with sildenafil, the protein levels of full-length PARP, β-Catenin and Hsp90 were time- and dose-dependent decreased in both SW480 and HCT116 cells (Figure 3C).

四、只要抑制hsp90--哪怕是达不到阈值的低水平抑制，哪怕这种低水平抑制本身并无抗癌活性--就能延缓乳腺癌内分泌治疗的耐药。
《HSP90 empowers evolution of resistance to hormonal therapy in human breast cancer models》
Guided by our previous work in pathogenic fungi, in which very modest HSP90 inhibition impairs resistance to mechanistically diverse antifungals, we examined the effect of similarly modest HSP90 inhibition on the emergence of resistance to antiestrogens in breast cancer models. Even though this degree of inhibition fell below the threshold for proteotoxic activation of the heat-shock response and had no overt anticancer activity on its own, it dramatically impaired the emergence of resistance to hormone antagonists both in cell culture and in mice. Our findings strongly support the clinical testing of combined hormone antagonist-low-level HSP90 inhibitor regimens in the treatment of metastatic estrogen receptor-positive breast cancer. At a broader level, they also provide promising proof of principle for a generalizable strategy to combat the pervasive problem of rapidly emerging resistance to molecularly targeted therapeutics.

五、西地那非能减轻他莫昔芬的肝毒性
《Nrf2 and NF-қB interplay in tamoxifen-induced hepatic toxicity: A promising therapeutic approach of sildenafil and low-dose γ radiation》
Tamoxifen-induced hepatotoxicity is an inevitable side effect during breast cancer treatment. Low-dose gamma irradiation (IRR) shows many beneficial effects by stimulating various biological processes. This study evaluates the possible effect of sildenafil and low-dose gamma radiation on liver damages as new treatment strategies. Group I (control), group II: (tamoxifen), group III: (tamoxifen + Sildenafil), group IV: (tamoxifen+ irradiation) and group V: (tamoxifen +Sildenafil + irradiation). Rats were sacrificed after 5 h from tamoxifen injection. Results showed that tamoxifen caused elevation in serum AST, ALT and ALP as well hepatic ROS, iNOS, MDA, Keap-1 and NF-Kb, in addition to diminution in hepatic Nrf2 and HO-1. Exposure to low-dose gamma radiation and sildenafil amended the alterations in the measured parameters in serum and tissue. Moreover, all results were confirmed by histopathological examination. In conclusion, sildenafil and low-dose gamma radiation can mitigate the toxicity induced by tamoxifen in liver tissues. Hence, this treatment could be further evaluated as a new approach for alleviating various liver disorders.

六、西地那非抑制芳香化酶，对HR阳性乳腺癌有一定的治疗作用
《Effect of sildenafil on human aromatase activity: From in vitro structural analysis to catalysis and inhibition in cells》
Sildenafil is found to bind to aromatase with a KD of 0.58 ± 0.05 μM acting as a partial and mixed inhibitor with a maximal inhibition of 35 ± 2%

乳腺癌患者用他莫昔芬时一般无病灶或者肿瘤负荷很轻；他莫昔芬往往也要长期使用（5-15年）；这种情况下联用副作用大的专门hsp90抑制剂如Pimitespib没必要。
西地那非副作用小，可长期连续使用（如治疗肺动脉高压）；因此可以把西地那非当做hsp90的替代药物来和他莫昔芬联用。
西地那非又能减轻他莫昔芬的肝毒性，本身又能抑制芳香化酶，相较其他hsp90的替代药物，西地那非跟他莫昔芬更配。