Suppression of p38-stress kinase sensitizes quiescent leukemic cells to anti-mitotic drugs by inducing proliferative responses in them

Abstract

Quiescent cells pose a formidable challenge in clinical management of leukemia, since they escape chemo-radiotherapy and become a source of post-therapy relapse. These cells may be refractory to various known growth-promoting signals, making it imperative to identify the biochemical signals necessary to coax them into mitosis. Using serum-starved cell lines as an experimental model of quiescent leukemic cells (QLCs), we demonstrate that a suppression of p38 stress kinase by pharmacological means forms a sufficient trigger to induce proliferative responses in the treated QLCs, even in the absence of any external growth-promoting stimulus. A robust expression of Ki67 and B23 was seen in treated cells, an effect clearly mediated through the activation of extra-cellular signal-regulated kinase (MEK/ERK) pathway. Commensurate with their proliferative status, the treated QLCs got sensitized to significantly low concentrations of anti-mitotic agents. Most importantly, primitive leukemic progenitors present in the mononuclear cells (MNCs) that were isolated from the peripheral blood of freshly diagnosed untreated acute myeloid leukemic (AML) patients got more efficiently killed by cytosine arabinoside (AraC), when the cells were pre-treated with a pharmacological inhibitor of p38. Our data strongly suggest that a suppression of p38 leads to the sensitization of QLCs to anti-mitotic drugs by triggering proliferative responses in them. This approach may have a potential clinical application.

Curcumin sensitizes quiescent leukemic cells to antimitotic drug 5-fluorouracil by inducing proliferative responses in them

“…Cells were starved in low serum (0.5% FBS) medium overnight to prepare Quiescent Leukemic Cells (QLCs) from them. [36] QLCs were subjected to various treatments as follows:…”

“…The data represent mean ± S.E.M of three independent experiments (** P ≤ 0.01) to treatment, and their presence is associated with relapses. [13,15,16] In 2008, Vaidya et al [36] showed that inhibition of p38 mitogen-associated protein kinase (MAPK) sensitizes the QLCs to antimitotic agents 5-FU and cytosine arabinoside (Ara-C). Since the treatment of QLCs with low concentrations of curcumin was pushing the cells into proliferation, we conjectured that this proliferative response could be translated to increase the sensitivity of the leukemic cells to antimitotic agents.…”

“…Based on our previous studies, [36] we wanted to examine whether the proliferative response induced by low concentrations of curcumin treatment would make the quiescent leukemic cells more susceptible to the mitotic inhibitor 5-FU. KG1a cells that were made quiescent by serum deprivation were first treated with low concentrations of curcumin (10 µg/mL and 20 µg/mL) and then exposed to 6 µg/mL (lowest concentration) of 5-FU.…”

“…KG1a cells that were made quiescent by serum deprivation were first treated with low concentrations of curcumin (10 µg/mL and 20 µg/mL) and then exposed to 6 µg/mL (lowest concentration) of 5-FU. [36] MTT assay was then carried out to assess the percent proliferation of the cells. It was observed [ Figure 4E] that QLCs that were treated with a combination of 5-FU and low concentrations of curcumin were more effectively killed (low percent proliferation: 60% and 65% for 10 µg/mL and 20 µg/mL, respectively) as compared to Figure 4A] or exposed to only curcumin [ Figure 4B], only 5-FU [ Figure 4C] and both curcumin and 5-FU [ Figure 4D].…”

p38 and cancer: Yang gets yin

“…In the study reported in this issue of Cancer Biology & Therapy by Vauidya et al 19 suppression of p38 by pharmacological inhibitors rescued growth-arrested cells to sensitivity to cytotoxic agents which are inactive on quiescent cells. This is an important example of how a modulator of cell signalling can be successfully used to enhance the effects of traditional cytotoxic chemotherapy.…”