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Abstract
Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy. To treat the disease successfully, new therapeutic strategies are urgently needed. One of these strategies can be the use of neurokinin-1 receptor (NK-1R) antagonists (e.g., aprepitant), because the substance P (SP)/NK-1R system is involved in cancer progression, including AML. AML patients show an up-regulation of the NK-1R mRNA expression; human AML cell lines show immunoreactivity for both SP and the NK-1R (it is overexpressed: the truncated isoform is more expressed than the full-length form) and, via this receptor, SP and NK-1R antagonists (aprepitant, in a concentration-dependent manner) respectively exert a proliferative action or an antileukemic effect (apoptotic mechanisms are triggered by promoting oxidative stress via mitochondrial Ca++ overload). Aprepitant inhibits the formation of AML cell colonies and, in combination with chemotherapeutic drugs, is more effective in inducing cytotoxic effects and AML cell growth blockade. NK-1R antagonists also exert an antinociceptive effect in myeloid leukemia-induced bone pain. The antitumor effect of aprepitant is diminished when the NF-κB pathway is overactivated and the damage induced by aprepitant in cancer cells is higher than that exerted in non-cancer cells. Thus, the SP/NK-1R system is involved in AML, and aprepitant is a promising antitumor strategy against this hematological malignancy. In this review, the involvement of this system in solid and non-solid tumors (in particular in AML) is updated and the use of aprepitant as an anti-leukemic strategy for the treatment of AML is also mentioned (a dose of aprepitant (>20 mg/kg/day) for a period of time according to the response to treatment is suggested). Aprepitant is currently used in clinical practice as an anti-nausea medication.
Highlights
Human myeloid leukemia shows an abnormal expansion of white blood cells in both bone marrow and blood [1,2,3]
In vitro and in vivo experiments have shown that the substance P (SP)/neurokinin-1 receptor (NK-1R) system, in a similar way, is involved in cancer progression in both solid and non-solid (AML) tumors
As tumor cells, including Acute myeloid leukemia (AML) cells, overexpress the NK-1R, the use of NK-1R antagonists could be an excellent common antitumor strategy against AML, since it is a heterogeneous disease that is difficult to treat due to the characteristics of the cytogenetic subtypes and the potentially-differing morphological and clinical properties from person to person. It seems that in all AML cases, the NK-1R will be overexpressed in tumor cells
Summary
Human myeloid leukemia (acute or chronic) shows an abnormal expansion of white blood cells in both bone marrow and blood [1,2,3]. Many data have shown that the NK-1R is a new potential target for the treatment of any type of tumor (both solid and non-solid), because it is known that NK-1R antagonists, via the NK-1R, induce apoptosis in cancer cells (Figure 1) [1,13,21,27,30,37,48,49]. In this sense, recent therapeutic strategies in which the SP/NK-1R is involved have shown promising results. As any cancer cell overexpresses the NK-1R and SP promotes the mitogenesis of these cells, a common therapeutic strategy against any tumor type (solid and non-solid) is possible: the use of NK-1R antagonists (Figure 1)
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