Abstract:Heat shock protein 27 (HSP27, HSPB1) is an anti-apoptotic protein characterized for its tumorigenic and metastatic properties, and now referenced as a major therapeutic target in many types of cancer. The biochemical properties of HSP27 rely on a structural oligomeric and dynamic organization that is important for its chaperone activity. Down-regulation by small interfering RNA or inhibition with a dominant-negative mutant efficiently counteracts the anti-apoptotic and protective properties of HSP27. However, … Show more
“…Our previous study showed that SW15 promotes cross-linking of HSP27 to form altered dimers, inhibiting oligomerization of HSP27 [ 13 ]. For sequential further studies for screening of more potent HSP27 cross linkers using synthetic compounds ( Supplementary Figure 1A ) in NCI-H460 cells, we selected 3 chromenone compounds with differing side chain structures, J2, J4 and YK-598-2 because they promoted different amounts of altered cross-linking of HSP27 in both cells and HSP27 protein system (Figure 1A and Supplementary Figure 1B and 1C ).…”
Section: Resultsmentioning
confidence: 99%
“…Small molecule, J2, which promotes altered cross-linking of HSP27, offer a promising approach for inhibition of HSP27, although further research is needed to evaluate the safety and efficacy of this compound in a clinical setting. However, one thing that J2 is more advanced than the previous ones such as SW15 or zerumbone [ 12 , 13 ] is that it can be used for i.p. injection in combined with conventional anticancer drugs.…”
Section: Discussionmentioning
confidence: 99%
“…Compounds were synthesized as described previously [ 13 , 24 ] or as in Supplementary Information . Taxol (Santa Cruz, sc-201439A), and tanespimycin (17-N-allylamino-17-demethoxygeldanamycin, 17-AAG) (Selleckchem, S1141) were dissolved in DMSO and diluted in cell culture medium.…”
Section: Methodsmentioning
confidence: 99%
“…We previously demonstrated that zerumbone (ZER), a cytotoxic component isolated from a natural product, Zingiber zerumbet , and SW15 a synthetic xanthone compound, induced cross-linking of the HSP27 protein by insertion between the disulfide bonds of HSP27. Altered cross-linking of HSP27 modified normal HSP27 dimerization, which resulted in a sensitizing effect to tumors after treatment with radiation (IR) [ 12 , 13 ]. Therefore, altered cross-linking strategy was suggested as a novel strategy for inhibition of HSP27-mediated resistance.…”
Heat shock protein 27 (HSP27, HSPB1) induces resistance to anticancer drugs in various cancer types, including non-small cell lung cancer (NSCLC). Therefore, pharmacological inhibition of HSP27 in NSCLC may be a good strategy for anticancer therapy. Unlike other HSPs such as HSP90 and HSP70, small molecule approaches for neutralization of HSP27 are not well established because of the absence of an ATP binding domain. Previously, small molecules with altered cross linking activity of HSP27, were identified to inhibit building a large oligomer led to sensitization in combination with radiation and chemotherapeutic drugs. In this study, a chromene compound, J2 that exhibited better cross-linking activity of HSP27 than xanthone compound, SW15 which was previously identified, was yielding sensitization to NSCLC cells with high expression of HSP27 when combined with HSP90 inhibitor and standard anticancer modalities such as taxol and cisplatin. In vivo xenograft system also showed sensitization activity of J2, as well as in vitro cell viability, cell death or apoptosis detection assay. For better druggability, several quinolone compounds, an (bio) isostere of chromone and one of well-known core in many marketed medicine, was designed and synthesized by replacement of oxygen with nitrogen in 4-pyron structure of J2. However, the cross linking activity of HSP27 disappeared by quinolone compounds and the sensitizing effects on the anticancer drugs disappeared as well, suggesting oxygene moiety of 4-pyron structure of J2 may be a pharmacophore for induction of cross linking of HSP27 and sensitization to cancer cells. In conclusion, combination of chemotherapy with small molecules that induces altered cross-linking of HSP27 may be a good strategy to overcome the resistance of anticancer drugs in HSP27-over-expressing cancer cells.
“…Our previous study showed that SW15 promotes cross-linking of HSP27 to form altered dimers, inhibiting oligomerization of HSP27 [ 13 ]. For sequential further studies for screening of more potent HSP27 cross linkers using synthetic compounds ( Supplementary Figure 1A ) in NCI-H460 cells, we selected 3 chromenone compounds with differing side chain structures, J2, J4 and YK-598-2 because they promoted different amounts of altered cross-linking of HSP27 in both cells and HSP27 protein system (Figure 1A and Supplementary Figure 1B and 1C ).…”
Section: Resultsmentioning
confidence: 99%
“…Small molecule, J2, which promotes altered cross-linking of HSP27, offer a promising approach for inhibition of HSP27, although further research is needed to evaluate the safety and efficacy of this compound in a clinical setting. However, one thing that J2 is more advanced than the previous ones such as SW15 or zerumbone [ 12 , 13 ] is that it can be used for i.p. injection in combined with conventional anticancer drugs.…”
Section: Discussionmentioning
confidence: 99%
“…Compounds were synthesized as described previously [ 13 , 24 ] or as in Supplementary Information . Taxol (Santa Cruz, sc-201439A), and tanespimycin (17-N-allylamino-17-demethoxygeldanamycin, 17-AAG) (Selleckchem, S1141) were dissolved in DMSO and diluted in cell culture medium.…”
Section: Methodsmentioning
confidence: 99%
“…We previously demonstrated that zerumbone (ZER), a cytotoxic component isolated from a natural product, Zingiber zerumbet , and SW15 a synthetic xanthone compound, induced cross-linking of the HSP27 protein by insertion between the disulfide bonds of HSP27. Altered cross-linking of HSP27 modified normal HSP27 dimerization, which resulted in a sensitizing effect to tumors after treatment with radiation (IR) [ 12 , 13 ]. Therefore, altered cross-linking strategy was suggested as a novel strategy for inhibition of HSP27-mediated resistance.…”
Heat shock protein 27 (HSP27, HSPB1) induces resistance to anticancer drugs in various cancer types, including non-small cell lung cancer (NSCLC). Therefore, pharmacological inhibition of HSP27 in NSCLC may be a good strategy for anticancer therapy. Unlike other HSPs such as HSP90 and HSP70, small molecule approaches for neutralization of HSP27 are not well established because of the absence of an ATP binding domain. Previously, small molecules with altered cross linking activity of HSP27, were identified to inhibit building a large oligomer led to sensitization in combination with radiation and chemotherapeutic drugs. In this study, a chromene compound, J2 that exhibited better cross-linking activity of HSP27 than xanthone compound, SW15 which was previously identified, was yielding sensitization to NSCLC cells with high expression of HSP27 when combined with HSP90 inhibitor and standard anticancer modalities such as taxol and cisplatin. In vivo xenograft system also showed sensitization activity of J2, as well as in vitro cell viability, cell death or apoptosis detection assay. For better druggability, several quinolone compounds, an (bio) isostere of chromone and one of well-known core in many marketed medicine, was designed and synthesized by replacement of oxygen with nitrogen in 4-pyron structure of J2. However, the cross linking activity of HSP27 disappeared by quinolone compounds and the sensitizing effects on the anticancer drugs disappeared as well, suggesting oxygene moiety of 4-pyron structure of J2 may be a pharmacophore for induction of cross linking of HSP27 and sensitization to cancer cells. In conclusion, combination of chemotherapy with small molecules that induces altered cross-linking of HSP27 may be a good strategy to overcome the resistance of anticancer drugs in HSP27-over-expressing cancer cells.
“…We have previously demonstrated that synthetic compounds zerumbone and SW-15 could induce abnormal cross-linking of the HSP27 protein. Altered crosslinking of HSP27 modifies normal HSP27 dimerization resulting in functional inhibition of HSP27, thereby sensitizing tumors to conventional radiation and chemotherapies 10 , 11 . As an continuous study to further optimize HSP27 inhibitors through abnormal dimerization of HSP27, we have additionally designed and synthesized a small number of chrome-4-one derivatives and found J2 (Supplementary Fig.…”
Radiation therapy has been used to treat over 70% of thoracic cancer; however, the method usually causes radiation pneumonitis. In the current study, we investigated the radioprotective effects of HSP27 inhibitor (J2) on radiation-induced lung inflammation in comparison to amifostine. In gross and histological findings, J2 treatment significantly inhibited immune cell infiltration in lung tissue, revealing anti-inflammatory potential of J2. Normal lung volume, evaluated by micro-CT analysis, in J2-treated mice was higher compared to that in irradiated mice. J2-treated mice reversed radiation-induced respiratory distress. However, amifostine did not show significant radioprotective effects in comparison to that of J2. In HSP27 transgenic mice, we observed increased immune cells recruitment and decreased volume of normal lung compared to wild type mice. Increased ROS production and oxidative stress after IR were down-regulated by J2 treatment, demonstrating antioxidant property of J2. The entire data of this study collectively showed that J2 may be an effective therapeutic agent for radiation-induced lung injury.
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