Targeting RAS-RAF pathway significantly improves antitumor activity of Rigosertib-derived platinum(IV) complexes and overcomes cisplatin resistance

RAS-RAF pathway presents a valuable target for the cancer treatment due to its important roles in the regulation of tumor proliferation, apoptosis and the obtained resistance. To explore such target a RAS/CRAF interference agent, was therefore conjugated with Pt(IV) prodrugs via ester bond, resultin...

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Published in:European journal of medicinal chemistry 2020-05, Vol.194, p.112269-112269, Article 112269
Main Authors: Liu, Zhikun, Wang, Meng, Wang, Hengshan, Fang, Lei, Gou, Shaohua
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Language:English
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Overcoming CDDP resistance
Pt(IV) complexes
RAS-RAF interaction Disruptors
RAS-Signaling and mitochondrial apoptosis pathways
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description RAS-RAF pathway presents a valuable target for the cancer treatment due to its important roles in the regulation of tumor proliferation, apoptosis and the obtained resistance. To explore such target a RAS/CRAF interference agent, was therefore conjugated with Pt(IV) prodrugs via ester bond, resulting in total eleven multifunctional Pt(IV) complexes. The complexes could target genomic DNA and disrupt the signaling transduction from RAS protein to CRAF so that block the mitogen-activated protein kinase (MAPK) signaling pathway. Experiments in vitro indicated that all of the Pt(IV) complexes showed potent anti-tumor activity with IC50 values ranged from 8 nM to 22.55 μM, which were significantly improved as compared with cisplatin (CDDP) whose IC50 values ranged from 5.45 μM to 9.05 μM. Among them, 26 exerted the best anti-tumor activity in vitro, which not only exhibited excellent cytotoxicity against normal tumor cells, but also against CDDP-resistance cell lines (e.g. A549/CDDP and SKOV-3/CDDP). Importantly, 26 only showed little effect on normal cell lines such as HUEVC and LO2. Besides, the following biological mechanisms studies demonstrated that 26 could efficiently enter. A549 cells, significantly arrest cell cycle at G2/M phase, disrupt the signaling pathway and trigger endogenous caspase apoptosis pathway. Furthermore, results of a xenograft subcutaneous model of A549 tumor showed that 26 could effectively decrease tumor growth rates without causing loss of bodyweight. Total 11 Pt(IV) compounds by introducing ON013100 onto hydroxyl ligand of Pt(IV) complexes derived from CDDP and oxaliplatin through ester bond were designed and synthesized. The conjugate 26 could effectively release Pt(II) complexes and RAS analogues to exert anti-tumor activity in novel pathway. The following biological studies revealed that 26 could efficiently disrupt the interaction between RAS and CRAF by specifically interacting with CRAF. Furthermore, 26 could apparently induce DNA damage and initiate endogenous caspase apoptosis pathway. Moreover, 26 also showed excellent anti-tumor effect in vivo. All the findings suggested that 26 may be considered as a novel antitumor candidate for further exploration. [Display omitted] •High cytotoxicity against A549 cells and CDDP-resistant A549 cancer cells with IC50 values at 8 nM and 9 nM, respectively.•26 could disrupt RAS-RAF signaling pathway and significant binding ability to CRAF with Kd value of 3.93 μM.•Inducing DNA platinatio
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To explore such target a RAS/CRAF interference agent, was therefore conjugated with Pt(IV) prodrugs via ester bond, resulting in total eleven multifunctional Pt(IV) complexes. The complexes could target genomic DNA and disrupt the signaling transduction from RAS protein to CRAF so that block the mitogen-activated protein kinase (MAPK) signaling pathway. Experiments in vitro indicated that all of the Pt(IV) complexes showed potent anti-tumor activity with IC50 values ranged from 8 nM to 22.55 μM, which were significantly improved as compared with cisplatin (CDDP) whose IC50 values ranged from 5.45 μM to 9.05 μM. Among them, 26 exerted the best anti-tumor activity in vitro, which not only exhibited excellent cytotoxicity against normal tumor cells, but also against CDDP-resistance cell lines (e.g. A549/CDDP and SKOV-3/CDDP). Importantly, 26 only showed little effect on normal cell lines such as HUEVC and LO2. Besides, the following biological mechanisms studies demonstrated that 26 could efficiently enter. A549 cells, significantly arrest cell cycle at G2/M phase, disrupt the signaling pathway and trigger endogenous caspase apoptosis pathway. Furthermore, results of a xenograft subcutaneous model of A549 tumor showed that 26 could effectively decrease tumor growth rates without causing loss of bodyweight. Total 11 Pt(IV) compounds by introducing ON013100 onto hydroxyl ligand of Pt(IV) complexes derived from CDDP and oxaliplatin through ester bond were designed and synthesized. The conjugate 26 could effectively release Pt(II) complexes and RAS analogues to exert anti-tumor activity in novel pathway. The following biological studies revealed that 26 could efficiently disrupt the interaction between RAS and CRAF by specifically interacting with CRAF. Furthermore, 26 could apparently induce DNA damage and initiate endogenous caspase apoptosis pathway. Moreover, 26 also showed excellent anti-tumor effect in vivo. All the findings suggested that 26 may be considered as a novel antitumor candidate for further exploration. [Display omitted] •High cytotoxicity against A549 cells and CDDP-resistant A549 cancer cells with IC50 values at 8 nM and 9 nM, respectively.•26 could disrupt RAS-RAF signaling pathway and significant binding ability to CRAF with Kd value of 3.93 μM.•Inducing DNA platination formation.•High potency to induce apoptosis through a mitochondrion-dependent pathway.•Excellent antitumor activity in xenograft mouse model with good safety profile.</description><identifier>ISSN: 0223-5234</identifier><identifier>EISSN: 1768-3254</identifier><identifier>DOI: 10.1016/j.ejmech.2020.112269</identifier><identifier>PMID: 32248002</identifier><language>eng</language><publisher>France: Elsevier Masson SAS</publisher><subject>Overcoming CDDP resistance ; Pt(IV) complexes ; RAS-RAF interaction Disruptors ; RAS-Signaling and mitochondrial apoptosis pathways</subject><ispartof>European journal of medicinal chemistry, 2020-05, Vol.194, p.112269-112269, Article 112269</ispartof><rights>2020 Elsevier Masson SAS</rights><rights>Copyright © 2020 Elsevier Masson SAS. 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To explore such target a RAS/CRAF interference agent, was therefore conjugated with Pt(IV) prodrugs via ester bond, resulting in total eleven multifunctional Pt(IV) complexes. The complexes could target genomic DNA and disrupt the signaling transduction from RAS protein to CRAF so that block the mitogen-activated protein kinase (MAPK) signaling pathway. Experiments in vitro indicated that all of the Pt(IV) complexes showed potent anti-tumor activity with IC50 values ranged from 8 nM to 22.55 μM, which were significantly improved as compared with cisplatin (CDDP) whose IC50 values ranged from 5.45 μM to 9.05 μM. Among them, 26 exerted the best anti-tumor activity in vitro, which not only exhibited excellent cytotoxicity against normal tumor cells, but also against CDDP-resistance cell lines (e.g. A549/CDDP and SKOV-3/CDDP). Importantly, 26 only showed little effect on normal cell lines such as HUEVC and LO2. Besides, the following biological mechanisms studies demonstrated that 26 could efficiently enter. A549 cells, significantly arrest cell cycle at G2/M phase, disrupt the signaling pathway and trigger endogenous caspase apoptosis pathway. Furthermore, results of a xenograft subcutaneous model of A549 tumor showed that 26 could effectively decrease tumor growth rates without causing loss of bodyweight. Total 11 Pt(IV) compounds by introducing ON013100 onto hydroxyl ligand of Pt(IV) complexes derived from CDDP and oxaliplatin through ester bond were designed and synthesized. The conjugate 26 could effectively release Pt(II) complexes and RAS analogues to exert anti-tumor activity in novel pathway. The following biological studies revealed that 26 could efficiently disrupt the interaction between RAS and CRAF by specifically interacting with CRAF. Furthermore, 26 could apparently induce DNA damage and initiate endogenous caspase apoptosis pathway. Moreover, 26 also showed excellent anti-tumor effect in vivo. All the findings suggested that 26 may be considered as a novel antitumor candidate for further exploration. 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To explore such target a RAS/CRAF interference agent, was therefore conjugated with Pt(IV) prodrugs via ester bond, resulting in total eleven multifunctional Pt(IV) complexes. The complexes could target genomic DNA and disrupt the signaling transduction from RAS protein to CRAF so that block the mitogen-activated protein kinase (MAPK) signaling pathway. Experiments in vitro indicated that all of the Pt(IV) complexes showed potent anti-tumor activity with IC50 values ranged from 8 nM to 22.55 μM, which were significantly improved as compared with cisplatin (CDDP) whose IC50 values ranged from 5.45 μM to 9.05 μM. Among them, 26 exerted the best anti-tumor activity in vitro, which not only exhibited excellent cytotoxicity against normal tumor cells, but also against CDDP-resistance cell lines (e.g. A549/CDDP and SKOV-3/CDDP). Importantly, 26 only showed little effect on normal cell lines such as HUEVC and LO2. Besides, the following biological mechanisms studies demonstrated that 26 could efficiently enter. A549 cells, significantly arrest cell cycle at G2/M phase, disrupt the signaling pathway and trigger endogenous caspase apoptosis pathway. Furthermore, results of a xenograft subcutaneous model of A549 tumor showed that 26 could effectively decrease tumor growth rates without causing loss of bodyweight. Total 11 Pt(IV) compounds by introducing ON013100 onto hydroxyl ligand of Pt(IV) complexes derived from CDDP and oxaliplatin through ester bond were designed and synthesized. The conjugate 26 could effectively release Pt(II) complexes and RAS analogues to exert anti-tumor activity in novel pathway. The following biological studies revealed that 26 could efficiently disrupt the interaction between RAS and CRAF by specifically interacting with CRAF. Furthermore, 26 could apparently induce DNA damage and initiate endogenous caspase apoptosis pathway. Moreover, 26 also showed excellent anti-tumor effect in vivo. All the findings suggested that 26 may be considered as a novel antitumor candidate for further exploration. [Display omitted] •High cytotoxicity against A549 cells and CDDP-resistant A549 cancer cells with IC50 values at 8 nM and 9 nM, respectively.•26 could disrupt RAS-RAF signaling pathway and significant binding ability to CRAF with Kd value of 3.93 μM.•Inducing DNA platination formation.•High potency to induce apoptosis through a mitochondrion-dependent pathway.•Excellent antitumor activity in xenograft mouse model with good safety profile.</abstract><cop>France</cop><pub>Elsevier Masson SAS</pub><pmid>32248002</pmid><doi>10.1016/j.ejmech.2020.112269</doi><tpages>1</tpages></addata></record>
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subjects Overcoming CDDP resistance
Pt(IV) complexes
RAS-RAF interaction Disruptors
RAS-Signaling and mitochondrial apoptosis pathways
title Targeting RAS-RAF pathway significantly improves antitumor activity of Rigosertib-derived platinum(IV) complexes and overcomes cisplatin resistance
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