The hematopoietic-specific beta1-tubulin is naturally resistant to 2-methoxyestradiol and protects patients from drug-induced myelosuppression.
Taxanes and other microtubule-targeting drugs (MTDs) represent one of the most effective classes of cancer chemotherapeutics. However, ultimately their utility is limited due to drug-induced myelosuppression. Here we identify 2-Methoxyestradiol (2ME2) as the first MTD able to specifically target tumor cells while sparing the bone marrow from dose-limiting, life-threatening toxicities. Following drug selection with 2ME2, epithelial cancer cells acquired a tubulin mutation at Vbeta236I that impaired the 2ME2-tubulin interaction and rendered cells resistant to 2ME2. We further show that the hematopoietic-specific Hbeta1 tubulin isotype naturally encodes Ibeta236 and is insensitive to 2ME2. Systemic administration of 2ME2 in C57BL6 mice revealed that there was no effect on bone marrow microtubules, in contrast to the taxane or Vinca alkaloid induced toxicities. Similar results were obtained upon drug treatment of human bone marrow and CD34-positive stem/progenitor cells. Herein, we describe the first isotype-targeted chemotherapeutic, setting a new paradigm for the entire class of MTDs, and providing a model that could allow the design of new tubulin inhibitors devoid of myelosuppression. The ability to design a drug with minimal side-effects would significantly augment the chances of clinical success by allowing the use of a truly therapeutic dose rather than the maximally tolerated.
Escuin
Daniel
D
Weill Medical College of Cornell University, Department of Hematology and Oncology, New York, NY, USA.
Burke
Patricia A
PA
McMahon-Tobin
Grainne
G
Hembrough
Todd
T
Wang
Yuefang
Y
Alcaraz
Ana A
AA
Leandro-García
Luis Javier
LJ
Rodríguez-Antona
Cristina
C
Snyder
James P
JP
Lavallee
Theresa M
TM
Giannakakou
Paraskevi
P
D000077584:2-Methoxyestradiol; D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity; D001952:Bridged-Ring Compounds / Q000633:toxicity; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D006410:Hematopoiesis; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008870:Microtubules / Q000187:drug effects; D008969:Molecular Sequence Data; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D013234:Stem Cells / Q000187:drug effects; D043823:Taxoids / Q000633:toxicity; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism*; D050257:Tubulin Modulators / Q000494:pharmacology*
D000970:Antineoplastic Agents; D001952:Bridged-Ring Compounds; D020033:Protein Isoforms; D043823:Taxoids; D014404:Tubulin; D050257:Tubulin Modulators; C080625:taxane; D004958:Estradiol; D000077584:2-Methoxyestradiol