Rapamycin and curcumin induce apoptosis in primary resting B chronic lymphocytic leukemia cells

Abstract

B chronic lymphocytic leukemia (B-CLL) cells exist in patients as slowly accumulating resting as well as proliferating B cells. In this study, we examined whether Rapamycin and Curcumin, two naturally occurring compounds shown to have apoptotic effects, could selectively induce apoptosis in resting B-CLL cells. Mononuclear cells isolated from patients with B-CLL were treated with these agents and analysed by AnnexinV/propidium iodide binding, caspase activity, and changes in bcl-2/Bax ratio. Rapamycin and curcumin significantly induced apoptosis in resting B-CLL cells obtained from patients with CLL. Furthermore, rapamycin and curcumin increased caspase 9, 3 and 7 activity, decreased anti-apoptotic bcl-2 levels, and increased the pro-apoptotic protein Bax. These data suggest rapamycin and curcumin may be an effective treatment for B-CLL and are of high clinical significance considering the growing population of patients and lack of efficient treatment for this malignant disease.

Curcumin derivatives: Molecular basis of their anti-cancer activity

“…Curcumin exhibits cancer growth inhibition both in vitro and in vivo [5,6]: it suppresses cell proliferation in a variety of cancer cell lines and it inhibits tumorigenesis [7][8][9][10][11][12][13][14][15][16][17]. Multiple mechanisms of action are likely responsible for Curcumin various effects on cancer cells: G1/S arrest and apoptosis induction have been observed other than the mitotic block in different tumor cell lines [18][19][20].…”

Perspectives on inhibiting mTOR as a future treatment strategy for hematological malignancies

“…Furthermore, other studies recently reported a pro-apoptotic effect of rapamycin in primary B-CLL cells, thereby emphasizing the therapeutic value of mTOR inhibition in this disease. 90,91 Finally, Zanesi and colleagues showed the ability of rapamycin to improve survival of CLL transgenic mouse. 92 Given these results, clinical trials are ongoing in CLL and results from two phase II clinical trials have been recently published.…”

The PI3K/mTOR inhibitor PF-04691502 induces apoptosis and inhibits microenvironmental signaling in CLL and the Eµ-TCL1 mouse model

“…However, single-isoform inhibitors against PI3Ka/b/d and pan-class-1 PI3K inhibitors in CLL cells have all been reported to induce apoptosis. 22,23 Pharmacologic inhibition of mTOR induces cell cycle arrest and apoptosis in CLL cells [24][25][26] ; however, prolonged inhibition of mTOR is known to disrupt negative feedback loops and cause increased AKT S473 activation in other malignancies. 27,28 Given the important role of both PI3K and mTOR in CLL cell survival, the dual pharmacologic inhibition of both class-1 PI3K and mTOR signaling may offer new therapeutic potential, with the possibility of deeper remissions or as an alternative after resistance to idelalisib.…”