John H Miller
PhD Stanford University I BA North Central College, Illinois
Although I trained in developmental biology at Stanford University for my PhD and in physiology at the University of California at San Diego in my postdoctoral positions, I acquired an interest in anticancer drug development through my connections with the natural product and synthetic chemists at VUW. My major scientific contribution has been to identify the mode of action of two important compounds isolated from marine sponges, peloruside and zampanolide. These bioactive compounds disrupt the function of a cell’s cytoskeletal component, the microtubule, have a nanomolar antimitotic effect on cells, and have good potential for further development as anticancer therapeutics. I am also investigating the use of microtubule-targeting agents in the treatment of Alzheimer’s disease and multiple sclerosis. In addition to these agents that disrupt microtubule function, my current research is directed toward heparan sulfate compounds that inhibit the enzyme heparanase, which plays an important role in cancer cell metastasis.
Mechanism of Action of Marine Natural Products: I am investigating the mode of action of microtubule-stabilizing agents isolated from marine sponges for development as anti-cancer drugs. We are also exploring the potential therapeutic use of these bioactive compounds in diseases of inflammation, such as multiple sclerosis, and in neurodegenerative diseases like Alzheimers Disease. I am currently focusing on interactions of these drugs with their primary and secondary protein targets, using semi-synthetic analogs to determine their structure-activity relationships.
Neurochemistry of Drug Abuse: I am also interested in the effects of MDMA (ecstasy), cannabis, and tobacco smoke extracts on brain neurochemistry. Currently we are investigating the links between cannabinoid receptors and opioid receptors and their effects on learning and memory.
John has been awarded a Life Membership of the Physiological Society of New Zealand in December 2018. Life membership is an honour reserved for selected members of the Society as recognition for distinguished service to the Society.
Wilmes A, Chan A, Rawson P, Jordan TW, Miller JH (2010) Paclitaxel effects on the proteome of HL-60 promyelocytic leukemic cells: Comparison to peloruside A. Investigational New Drugs. In Press 10.9.10, doi: 10.1007/s10637-010-9540-1
Kanakkanthara A, Wilmes A, O'Brate A, Escuin D, Chan A, Gjyrezi A, Crawford J, Rawson P, Kivell B, Northcote PT, Hamel E, Giannakakou P, Miller JH (2011) Peloruside- and laulimalide-resistant human ovarian carcinoma cells have βI-tubulin mutations and altered expression of βII- and βIII-tubulin isotypes. Molecular Cancer Therapeutics 10: 1419-1429
Chan A, Andreae P, Northcote PT, Miller JH (2011) Peloruside A inhibits microtubule dynamics in a breast cancer cell line MCF7. Investigational New Drugs 29: 615-626
Wilmes A, Rawson P, Peng L, McLauchlan D, Northcote PT, Jordan TW, Miller JH (2011) Effects of the microtubule stabilizing agent peloruside A on the proteome of HL-60 cells. Investigational New Drugs 29: 544-553
Wilmes A, O’Sullivan D, Chan A, Chandrahasen C, Paterson I, Northcote PT, La Flamme AC, Miller JH (2010) Synergistic interactions between peloruside A and other microtubule-stabilizing and destabilizing agents in cultured human ovarian carcinoma cells and murine T cells. Cancer Chemotherapy and Pharmacology, 68: 117-126
Kivell B, Day D, Bosch P, Schenk S, Miller J (2010) MDMA causes a redistribution of serotonin transporter from the cell surface to the intracellular compartment by a mechanism independent of p38-MAPK activation. Neuroscience 168: 82-95
Miller JH, Singh AJ, Northcote PT (2010) Microtubule-stabilizing drugs from marine sponges: Focus on peloruside and zampanolide. Marine Drugs 8: 1059-1079
Field JJ, Singh AJ, Kanakkanthara A, Halafihi T, Northcote, PT, Miller JH (2009) Microtubule-stabilizing activity of Zampanolide, a potent macrolide isolated from the Tongan marine sponge Cacospongia mycofijiensis. Journal of Medicinal Chemistry 52: 7328-7332