Figure 3.

Chemoresistance pathways and chemosensitization in Ara-C chemoresistant cells. (a) Ara-C chemoresistance pathways. Leukemic cells develop different MOCs that determine the acquisition of resistance to Ara-C: the overexpression (red and bold) of oncogenes such as RAS, NFkB, MAPK and c-Myc, as well as key modulators of cell function such as AkT and mTOR lead to the activation of oncogenic pathways (CREB overexpression), antiapoptotic factors (Bcl2, Mcl1, Bcl-xL), changes in metabolism (blocking of NSP by dCK depletion and transition to DNSP via the RNP enzyme), and dysregulation of the cell cycle (via overexpression of CDKs and cyclines). This set of MOCs, in addition to the aberrant expression of ABC transporters, is responsible for the cell efflux of chemotherapy drugs and is the cause of chemoresistance and relapse. (b) Proposal to induce cytotoxicity in Ara-C chemoresistant AML cells. In the presence of standard doses of Ara-C, the addition of (i) MnKI-8e, (ii) emodin, (iii) metformin or (iv) niclosamide (blue boxes) produces either chemosensitization, a synergistic antitumor effect, apoptosis, blocking mutated pathways (mTOR and CREB), or negative regulation of oncogenes (NFkB, AkT, c-Myc) and key regulators of cell function (MAPK) compared to Ara-C alone, or in combination; (v) heteronemin or (vi) PD0332991 (blue boxes) sensitizes resistant AML cells to reduced or subtoxic concentrations of Ara-C. Standard therapeutic concentrations of Ara-C in the presence of (vi) hydroxyurea and azidothymidine (HU + AZT) (blue boxes) are antileukemic due to the blockade of the RNP enzyme, a key enzyme in the DNSP pathway. Nonmalignant cells are resistant to damage because they have a functional NSP pathway. The use of sorafenib or MK571 efficiently blocks the efflux of Ara-C and Ara-CTP by inhibiting ABC transporters. Some MOCs prevail (metabolic switches), but the therapeutic effect of Ara-C is not compromised.