PI3K/Akt inhibition modulates multidrug resistance

     Multidrug resistance (MDR), characterized by cancer cell resistance to multiple  chemotherapeutic drugs, is a major clinical obstacle in the treatment of hematological malignancies.

     Chemotherapeutic drugs has been identified to induce a variety of cellular responses that impact on tumor cell proliferation and survival. On the other hand, many investigators have comfirmed that the PI3K/Akt pathway is associated with chemoresistance in cancer cells. A recent report has demonstrated that MRP-1 efflux is inhibited by the PI3K inhibitor wortmannin in acute myelogenous leukemia [1]. While, another PI3K inhibitor, LY294002, can block Pgp efflux in mouse leukemic cell lines[2]. Thus, the role of PI3K and corresponding mechanism in MDR need further studies.

     About this correlation, García and his group reported their study results in a recent paper[3]. As expected, they found higher PI3K/Akt activity in drug resistant cell lines. PI3K/Akt inhibition after wortmannin or LY294002 treatment leads to higher apoptosis induction in the resistant cell lines. Next, the effect of co-treatment with the chemotherapeutic agents and PI3K/Akt inhibitors was evaluated on apoptosis,  and PI3K/Akt inhibition was found to sensitize cell lines to vincristine (VCR)-induced apoptosis. Further pharmacokinetic study indicated that PI3K inhibitors such as wortmannin and LY294002 are able to inhibit Pgp efflux in the resistant cell lines.
     In summary, PI3K inhibitors, including wortmannin or LY294002, alleviate MDR in cancer cells by both PI3K/Akt and Pgp function inhibition. PI3K/Akt signaling may be considered as an attractive target and the corresponding inhibitor is undoubtedly a good candidate against multidrug resistance.

[1]. Leukemia 2007;21:427–38.
[2]. Eur J Pharm Sci 2006;29:426–34.
[3]. Leukemia Res 2009;33:288–296.

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Cat.No. Product Name Information Publications Customer Product Validation
S1105 LY294002 LY294002 (SF 1101, NSC 697286) is the first synthetic molecule known to inhibit PI3Kα/δ/β with IC50 of 0.5 μM/0.57 μM/0.97 μM, respectively; more stable in solution than Wortmannin, and also blocks autophagosome formation. It not only binds to class I PI3Ks and other PI3K-related kinases, but also to novel targets seemingly unrelated to the PI3K family. LY294002 also inhibits CK2 with IC50 of 98 nM. LY294002 is a non-specific DNA-PKcs inhibitor and activates autophagy and apoptosis. (1310) (15)

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