2. Academic Validation
  3. New ruthenium-xanthoxylin complex eliminates colorectal cancer stem cells by targeting the heat shock protein 90 chaperone

New ruthenium-xanthoxylin complex eliminates colorectal cancer stem cells by targeting the heat shock protein 90 chaperone

  • Cell Death Dis. 2023 Dec 15;14(12):832. doi: 10.1038/s41419-023-06330-w.
Luciano de S Santos 1,  Valdenizia R Silva 1,  Maria V L de Castro 1,  Rosane B Dias 1 2,  Ludmila de F Valverde 1,  Clarissa A G Rocha 1 2,  Milena B P Soares 1 3,  Claudio A Quadros 4 5,  Edjane R Dos Santos 6,  Regina M M Oliveira 7,  Rose M Carlos 8,  Paulo C L Nogueira 9,  Daniel P Bezerra 10
Affiliations

Affiliations

  • 1 Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, BA, 40296-710, Brazil.
  • 2 Department of Propedeutics, School of Dentistry of the Federal University of Bahia, Salvador, BA, 40110-909, Brazil.
  • 3 SENAI Institute of Innovation (ISI) in Health Advanced Systems, University Center SENAI/CIMATEC, Salvador, BA, 41650-010, Brazil.
  • 4 São Rafael Hospital, Rede D'Or/São Luiz, Salvador, BA, 41253-190, Brazil.
  • 5 Bahia State University, Salvador, BA, 41150-000, Brazil.
  • 6 Institute of Natural, Human and Social Sciences, Federal University of Mato Grosso, Sinop, MT, 78557-267, Brazil.
  • 7 Coordination of Science and Technology, Balsas Science Center, Federal University of Maranhão, Balsas, MA, 65800-000, Brazil.
  • 8 Department of Chemistry, Federal University of São Carlos, São Carlos, SP, 13561-901, Brazil.
  • 9 Department of Chemistry, Federal University of Sergipe, São Cristóvão, SE, 49100-000, Brazil.
  • 10 Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, BA, 40296-710, Brazil. [email protected].
PMID: 38102125 DOI: 10.1038/s41419-023-06330-w
Abstract

In this work, we describe a novel ruthenium-xanthoxylin complex, [Ru(phen)2(xant)](PF6) (RXC), that can eliminate colorectal Cancer (CRC) stem cells by targeting the chaperone HSP90. RXC exhibits potent cytotoxicity in Cancer cell lines and primary Cancer cells, causing Apoptosis in HCT116 CRC cells, as observed by cell morphology, YO-PRO-1/PI staining, internucleosomal DNA fragmentation, mitochondrial depolarization, and PARP cleavage (Asp214). Additionally, RXC can downregulate the HSP90AA1 and HSP90B1 genes and the expression of HSP90 protein, as well as the expression levels of its downstream/client elements Akt1, Akt (pS473), mTOR (pS2448), 4EBP1 (pT36/pT45), GSK-3β (pS9), and NF-κB p65 (pS529), implying that these molecular chaperones can be molecular targets for RXC. Moreover, this compound inhibited clonogenic survival, the percentage of the CRC stem cell subpopulation, and colonosphere formation, indicating that RXC can eliminate CRC stem cells. RXC reduced cell migration and invasion, decreased vimentin and increased E-cadherin expression, and induced an autophagic process that appeared to be cytoprotective, as Autophagy inhibitors enhanced RXC-induced cell death. In vivo studies showed that RXC inhibits tumor progression and experimental metastasis in mice with CRC HCT116 cell xenografts. Taken together, these results highlight the potential of the ruthenium complex RXC in CRC therapy with the ability to eliminate CRC stem cells by targeting the chaperone HSP90.

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