title: α- and β-Santalols Directly Interact with Tubulin and Cause Mitotic Arrest and Cytotoxicity in Oral Cancer Cells.
abstract: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, with no major advancements in treatment over the past 40 years. The current study explores the biological effects of East Indian sandalwood oil (EISO) and its two major constituents, α- and β-santalol, against a variety of HNSCC lines. All three agents exhibited cytotoxic effects and caused accumulation of cells in the G2/M phases of the cell cycle. Additionally, treatment with these agents caused formation of multipolar mitotic spindles similar to those observed upon treatment of cells with compounds that affect microtubule polymerization. Indeed, the santalols, as well as EISO, inhibited the polymerization of purified tubulin, indicating for the first time that these compounds have the ability to directly bind to tubulin and affect microtubule formation. Modeling studies suggest that the santalols can weakly bind to the colchicine site on tubulin, and topical administration of EISO to a HNSCC xenograft inhibited tumor growth with no observed toxicities. Therefore, santalols can directly interact with tubulin to inhibit the polymerization of microtubules, similarly to established classes of chemotherapeutic agents, albeit with greatly reduced potency that is not associated with the classic toxicity associated with most other compounds that interact directly with tubulin.
authors.affiliation: †Department of Pharmacology, University of Texas Health Science Center, San Antonio, Texas 78229, United States.
authors.forename: Brigette
authors.initials: B
authors.lastname: Lee
authors.affiliation: ‡Southwest Research Institute, 6220 Culebra Road, San Antonio, Texas 78238, United States.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Bohmann
authors.affiliation: ‡Southwest Research Institute, 6220 Culebra Road, San Antonio, Texas 78238, United States.
authors.forename: Tony
authors.initials: T
authors.lastname: Reeves
authors.affiliation: §Santalis Pharmaceuticals, 18618 Tuscany Stone, Suite 100, San Antonio, Texas 78258, United States.
authors.forename: Corey
authors.initials: C
authors.lastname: Levenson
authors.affiliation: †Department of Pharmacology, University of Texas Health Science Center, San Antonio, Texas 78229, United States.
authors.forename: April L
authors.initials: AL
authors.lastname: Risinger
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D003078:Colchicine / Q000494:pharmacology; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D008870:Microtubules / Q000187:drug effects; D008938:Mitosis / Q000187:drug effects; D008958:Models, Molecular; D015394:Molecular Structure; D009062:Mouth Neoplasms / Q000188:drug therapy*; D000081223:Polycyclic Sesquiterpenes; D032123:Santalum / Q000737:chemistry*; D012717:Sesquiterpenes / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D014404:Tubulin / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D000081223:Polycyclic Sesquiterpenes; D012717:Sesquiterpenes; D014404:Tubulin; C043206:santalol; D003078:Colchicine