313 Resistance to the microtubule-stabilizing agents, peloruside A and laulimalide, is associated with multiple b-tubulin alterations

Kanakkanthara, Arun; Crawford, James J.; Rawson, Pisana; Kivell, Bronwyn M.; Northcote, Peter T.; Miller, J.H.

doi:10.1016/s1359-6349(10)72020-6

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“…The recombinant microtubule composed of the alpha and beta tubulins from T. cuspidata was found to be more tolerant to taxol more than the microtubule from HEK293T cells. The treatment of cancer cells with microtubule-associated drugs, including taxol, 5) peloruside A, 33) and laulimalide, 34) facilitates the acquisition of the mutations in the beta tubulin of the resistant cells, although we cloned the alpha and beta tubulin cDNAs from HEK293T cells in the absence of taxol. In addition, the deduced amino acid sequences of alpha and beta human tubulins were identical to those registered in the database (Accession Number: NP_006073.2 and NP_821133.1), suggesting that the recombinant human microtubule is supposedly sensitive to taxol.…”

Section: Discussionmentioning

confidence: 99%

Expression of recombinant alpha and beta tubulins from the yew Taxus cuspidata and analysis of the microtubule assembly in the presence of taxol

Kudo

Abe

Ito

et al. 2014

Bioscience, Biotechnology, and Biochemistry

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Taxol was originally isolated from the yew Taxus brevifolia. Because taxol inhibits the depolymerization of microtubules, the presence of a self-resistance mechanism in Taxus spp. was hypothesized. The cloning of the cDNA for alpha and beta tubulins from Taxus cuspidata and those from the human embryonic kidney cell line HEK293T revealed that the 26Asp, 359Arg, and 361Leu residues in the human beta tubulin, which are important for taxol binding, were replaced with Glu, Trp, and Met in the beta tubulin of T. cuspidata, respectively. The microtubule assembly of the recombinant alpha and beta tubulins was monitored turbidimetrically, and the results clearly demonstrated that the microtubule from T. cuspidata is less sensitive to taxol than that from HEK293T cells. The Taxus microtubule composed of the wild-type alpha tubulin and the beta tubulin with the E26D mutation restored the sensitivity to taxol. We thus postulated that the mutation identified in the beta tubulin of T. cuspidata plays a role in the self-resistance of this species against taxol.

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Section: Discussionmentioning

confidence: 99%