TY - JOUR
T1 - PI3K/p110δ is a novel therapeutic target in multiple myeloma
AU - Ikeda, Hiroshi
AU - Hideshima, Teru
AU - Fulciniti, Mariateresa
AU - Perrone, Giulia
AU - Miura, Naoya
AU - Yasui, Hiroshi
AU - Okawa, Yutaka
AU - Kiziltepe, Tanyel
AU - Santo, Loredana
AU - Vallet, Sonia
AU - Cristea, Diana
AU - Calabrese, Elisabetta
AU - Gorgun, Gullu
AU - Raje, Noopur S.
AU - Richardson, Paul
AU - Munshi, Nikhil C.
AU - Lannutti, Brian J.
AU - Puri, Kamal D.
AU - Giese, Neill A.
AU - Anderson, Kenneth C.
PY - 2010/9/2
Y1 - 2010/9/2
N2 - In this study, we demonstrate expression and examined the biologic sequelae of PI3K/p110δ signaling in multiple myeloma (MM). Knockdown of p110δ by small interfering RNA caused significant inhibition of MM cell growth. Similarly, p110δ specific small molecule inhibitor CAL-101 triggered cytotoxicity against LB and INA-6 MM cell lines and patient MM cells, associated with inhibition of Akt phosphorylation. In contrast, CAL-101 did not inhibit survival of normal peripheral blood mononuclear cells. CAL-101 overcame MM cell growth conferred by interleukin-6, insulin-like growth factor-1, and bone marrow stromal cell coculture. Interestingly, inhibition of p110δ potently induced autophagy. The in vivo inhibition of p110δ with IC488743 was evaluated in 2 murine xenograft models of human MM: SCID mice bearing human MM cells subcutaneously and the SCID-hu model, in which human MM cells are injected within a human bone chip implanted subcutaneously in SCID mice. IC488743 significantly inhibited tumor growth and prolonged host survival in both models. Finally, combined CAL-101 with bortezomib induced synergistic cytotoxicity against MM cells. Our studies therefore show that PI3K/p110δ is a novel therapeutic target in MM and provide the basis for clinical evaluation of CAL-101 to improve patient outcome in MM.
AB - In this study, we demonstrate expression and examined the biologic sequelae of PI3K/p110δ signaling in multiple myeloma (MM). Knockdown of p110δ by small interfering RNA caused significant inhibition of MM cell growth. Similarly, p110δ specific small molecule inhibitor CAL-101 triggered cytotoxicity against LB and INA-6 MM cell lines and patient MM cells, associated with inhibition of Akt phosphorylation. In contrast, CAL-101 did not inhibit survival of normal peripheral blood mononuclear cells. CAL-101 overcame MM cell growth conferred by interleukin-6, insulin-like growth factor-1, and bone marrow stromal cell coculture. Interestingly, inhibition of p110δ potently induced autophagy. The in vivo inhibition of p110δ with IC488743 was evaluated in 2 murine xenograft models of human MM: SCID mice bearing human MM cells subcutaneously and the SCID-hu model, in which human MM cells are injected within a human bone chip implanted subcutaneously in SCID mice. IC488743 significantly inhibited tumor growth and prolonged host survival in both models. Finally, combined CAL-101 with bortezomib induced synergistic cytotoxicity against MM cells. Our studies therefore show that PI3K/p110δ is a novel therapeutic target in MM and provide the basis for clinical evaluation of CAL-101 to improve patient outcome in MM.
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UR - http://www.scopus.com/inward/citedby.url?scp=77956592891&partnerID=8YFLogxK
U2 - 10.1182/blood-2009-06-222943
DO - 10.1182/blood-2009-06-222943
M3 - Article
C2 - 20505158
AN - SCOPUS:77956592891
SN - 0006-4971
VL - 116
SP - 1460
EP - 1468
JO - Blood
JF - Blood
IS - 9
ER -