title: Honokiol bis-dichloroacetate (Honokiol DCA) demonstrates activity in vemurafenib-resistant melanoma in vivo.
abstract: The majority of human melanomas bears BRAF mutations and thus is treated with inhibitors of BRAF, such as vemurafenib. While patients with BRAF mutations often demonstrate an initial dramatic response to vemurafenib, relapse is extremely common. Thus, novel agents are needed for the treatment of these aggressive melanomas. Honokiol is a small molecule compound derived from Magnolia grandiflora that has activity against solid tumors and hematopoietic neoplasms. In order to increase the lipophilicity of honokiol, we have synthesized honokiol DCA, the dichloroacetate ester of honokiol. In addition, we synthesized a novel fluorinated honokiol analog, bis-trifluoromethyl-bis-(4-hydroxy-3-allylphenyl) methane (hexafluoro). Both compounds exhibited activity against A375 melanoma in vivo, but honokiol DCA was more active. Gene arrays comparing treated with vehicle control tumors demonstrated induction of the respiratory enzyme succinate dehydrogenase B (SDHB) by treatment, suggesting that our honokiol analogs induce respiration in vivo. We then examined its effect against a pair of melanomas, LM36 and LM36R, in which LM36R differs from LM36 in that LM36R has acquired vemurafenib resistance. Honokiol DCA demonstrated in vivo activity against LM36R (vemurafenib resistant) but not against parental LM36. Honokiol DCA and hexafluoro inhibited the phosphorylation of DRP1, thus stimulating a phenotype suggestive of respiration through mitochondrial normalization. Honokiol DCA may act in vemurafenib resistant melanomas to increase both respiration and reactive oxygen generation, leading to activity against aggressive melanoma in vivo.
authors.affiliation: Department of Dermatology, Emory School of Medicine, and Winship Cancer Institute, Atlanta, GA, USA.
authors.forename: Michael Y
authors.initials: MY
authors.lastname: Bonner
authors.affiliation: Department of Dermatology, Emory School of Medicine, and Winship Cancer Institute, Atlanta, GA, USA.
authors.forename: Isabella
authors.initials: I
authors.lastname: Karlsson
authors.affiliation: Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori via Venezian, Milan, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Rodolfo
authors.affiliation: Department of Urology, Emory School of Medicine, Atlanta, GA, USA.
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Arnold
authors.affiliation: Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori via Venezian, Milan, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Vergani
authors.affiliation: Department of Dermatology, Emory School of Medicine, and Winship Cancer Institute, Atlanta, GA, USA.|Department of Dermatology, Veterans Affairs Medical Center, Decatur, GA, USA.
authors.forename: Jack L
authors.initials: JL
authors.lastname: Arbiser
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D007211:Indoles; D017705:Lignans / Q000494:pharmacology*; D008545:Melanoma; D051379:Mice; D015398:Signal Transduction / Q000187:drug effects*; D013449:Sulfonamides; D000077484:Vemurafenib; D023041:Xenograft Model Antitumor Assays; D000498:Allyl Compounds; D010636:Phenols
chemical_list: D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D001713:Biphenyl Compounds; D007211:Indoles; D017705:Lignans; D013449:Sulfonamides; D000077484:Vemurafenib; C005499:honokiol; D000498:Allyl Compounds; D010636:Phenols
keywords: melanoma; mitochondria; reactive oxygen; vemurafenib-resistant; xenographs