PM060184, a new tubulin binding agent with potent antitumor activity including P-glycoprotein over-expressing tumors.
PM060184 belongs to a new family of tubulin-binding agents originally isolated from the marine sponge Lithoplocamia lithistoides. This compound is currently produced by total synthesis and is under evaluation in clinical studies in patients with advanced cancer diseases. It was recently published that PM060184 presents the highest known affinities among tubulin-binding agents, and that it targets tubulin dimers at a new binding site. Here, we show that PM060184 has a potent antitumor activity in a panel of different tumor xenograft models. Moreover, PM060184 is able to overcome P-gp mediated resistance in vivo, an effect that could be related to its high binding affinity for tubulin. To gain insight into the mechanism responsible of the observed antitumor activity, we have characterized its molecular and cellular effects. We have observed that PM060184 is an inhibitor of tubulin polymerization that reduces microtubule dynamicity in cells by 59%. Interestingly, PM060184 suppresses microtubule shortening and growing at a similar extent. This action affects cells in interphase and mitosis. In the first case, the compound induces a disorganization and fragmentation of the microtubule network and the inhibition of cell migration. In the second case, it induces the appearance of multipolar mitosis and lagging chromosomes at the metaphase plate. These effects correlate with prometaphase arrest and induction of caspase-dependent apoptosis or appearance of cells in a multinucleated interphase-like state unrelated to classical apoptosis pathways. Taken together, these results indicate that PM060184 represents a new tubulin binding agent with promising potential as an anticancer agent.
PharmaMar S.A., Avda de los Reyes 1, Polígono Industrial La Mina, Colmenar Viejo, 28770 Madrid, Spain.
Marta
M
Martínez-Díez
PharmaMar S.A., Avda de los Reyes 1, Polígono Industrial La Mina, Colmenar Viejo, 28770 Madrid, Spain.
María José
MJ
Guillén-Navarro
Centro de Investigaciones Biológicas, CSIC, Ramiro de Maeztu 9, 28040 Madrid, Spain.
Benet
B
Pera
Centre Léon Bérard, Lyon F-69373, France.
Benjamin Pierre
BP
Bouchet
PharmaMar S.A., Avda de los Reyes 1, Polígono Industrial La Mina, Colmenar Viejo, 28770 Madrid, Spain.
Juan Fernando
JF
Martínez-Leal
Centro de Investigaciones Biológicas, CSIC, Ramiro de Maeztu 9, 28040 Madrid, Spain.
Isabel
I
Barasoain
PharmaMar S.A., Avda de los Reyes 1, Polígono Industrial La Mina, Colmenar Viejo, 28770 Madrid, Spain.
Carmen
C
Cuevas
Centro de Investigaciones Biológicas, CSIC, Ramiro de Maeztu 9, 28040 Madrid, Spain.
Jose M
JM
Andreu
PharmaMar S.A., Avda de los Reyes 1, Polígono Industrial La Mina, Colmenar Viejo, 28770 Madrid, Spain.
Luis Francisco
LF
García-Fernández
Centro de Investigaciones Biológicas, CSIC, Ramiro de Maeztu 9, 28040 Madrid, Spain.
J Fernando
JF
Díaz
PharmaMar S.A., Avda de los Reyes 1, Polígono Industrial La Mina, Colmenar Viejo, 28770 Madrid, Spain.
Pablo
P
Avilés
PharmaMar S.A., Avda de los Reyes 1, Polígono Industrial La Mina, Colmenar Viejo, 28770 Madrid, Spain. Electronic address: cgalmarini@pharmamar.com.
Carlos M
CM
Galmarini
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D018385:Centrosome / Q000187:drug effects / Q000648:ultrastructure; D005260:Female; D007399:Interphase; D008819:Mice, Nude; D008870:Microtubules / Q000187:drug effects / Q000648:ultrastructure; D061065:Polyketides / Q000494:pharmacology*; D049468:Prometaphase / Q000187:drug effects; D011753:Pyrones / Q000494:pharmacology*; D008941:Spindle Apparatus / Q000187:drug effects / Q000648:ultrastructure; D050257:Tubulin Modulators / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D061065:Polyketides; D011753:Pyrones; D050257:Tubulin Modulators; C586200:plocabulin
Antimitotic agents; Cancer therapy; Microtubules; P-glycoprotein; Polymerization inhibitors; Tubulin modulators