The Neurokinin-1 Receptor Antagonist Aprepitant, a New Drug for the Treatment of Hematological Malignancies: Focus on Acute Myeloid Leukemia

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.

The Neurokinin-1 Receptor Antagonist Aprepitant: An Intelligent Bullet against Cancer?

“…Cancer cells express both SP and the NK-1R, and it is known that the SP/NK-1R system plays an important role in cancer since it is involved in tumor growth and development (both solid and non-solid) [2,28]; this has been demonstrated in many in vitro and in vivo experiments [2,3,16,17,27,28]. SP, via the NK-1R, exerts, in cancer cells, the following actions: mitogenesis, migration (invasion and metastasis), anti-apoptotic effects and an increase in the glycolytic rate (tumor cells increase their metabolism due to the glucose obtained; this mechanism is called the Warburg effect).…”

“…Aprepitant, in a concentration-dependent manner, is a broad-spectrum antitumor drug, as it promotes apoptotic mechanisms (Table 2) in many human cancer types such as colon, gastric, laryngeal and pancreatic carcinomas; esophageal squamous cell carcinoma; B-and T-cell acute lymphoblastic leukemias; retinoblastoma; neuroblastoma; glioma; osteosarcoma; acute or chronic myeloid leukemias; melanoma; breast cancer; and hepatoblastoma and lung cancer (small and non-small cell) [14][15][16][17]27,28,56,72,[82][83][84][85]. In many cases, maximum inhibition (100%) was observed when aprepitant was administered at a concentration of ≥70 µM (Table 2) [83].…”

“…Shows few contraindications (co-administration of cisapride/pimozide, hypersensitivity) [13,111,115] A relative contraindication occurs when co-administered with dexamethasone, oral hormonal contraceptives, benzodiazepines, ketoconazole or warfarin [111] Aprepitant's therapeutic index is very high, and cases showing a toxic effect due to an overdose of the drug are rare [111] Does not affect QTc intervals [111] A high dose of aprepitant: proliferation of normal cells was not affected [28,82] A high dose of aprepitant (300 mg/day; 1140 mg/day for 45 days): safe and well tolerated [5,111,117] The damage exerted by aprepitant was higher in cancer cells than in normal cells [82] Lymphocytes: IC 50 ten-fold higher than that for cancer cells [82] Fibroblasts: IC 50 higher than the IC 50 for cancer cells [83] Human breast epithelial cells: IC 50 > 90 µM, three times higher than the IC 50 for breast cancer cells and higher than the IC 100 for these tumor cells [17] Non-tumor cells: IC 50 (60 µM) and IC 100 (90 µM); IC 100 for cancer cells: 50 µM [6,83] In several experiments, the safety of aprepitant has been demonstrated. Thus, the proliferation of normal cells (e.g., lymphocytes) was not affected after the administration of a high dose of aprepitant [28,82], and in patients, the administration of high doses of aprepitant (300 mg/day; 1140 mg/day for 45 days) was safe and well tolerated (Table 3) [5,111,117]. It has also been reported that the IC 50 for lymphocytes is ten-fold higher than that for cancer cells, and consequently, the damage exerted by aprepitant was higher in cancer cells than in normal cells (Table 3) [82].…”

“…In several experiments, the safety of aprepitant has been demonstrated. Thus, the proliferation of normal cells (e.g., lymphocytes) was not affected after the administration of a high dose of aprepitant [ 28 , 82 ], and in patients, the administration of high doses of aprepitant (300 mg/day; 1140 mg/day for 45 days) was safe and well tolerated ( Table 3 ) [ 5 , 111 , 117 ]. It has also been reported that the IC 50 for lymphocytes is ten-fold higher than that for cancer cells, and consequently, the damage exerted by aprepitant was higher in cancer cells than in normal cells ( Table 3 ) [ 82 ].…”

“…In addition, many data have demonstrated the involvement of the SP/NK-1R system in cancer [2,3,19,27,28]. For example, SP is a universal mitogen in tumor cells, and in a concentration-dependent manner, non-peptide NK-1R antagonists (e.g., aprepitant, L-733,060, L-732,138, CP 96,345 and SR-140,333; it is important to note that these compounds show different chemical compositions) exert antitumor actions against many human cancer cell lines (e.g., glioma, neuroblastoma, osteosarcoma, retinoblastoma, breast cancer (including triple-negative breast cancer cells), gastric cancer, pancreatic cancer, lung cancer (small-and non-small-cell lung cancer), colon cancer, larynx cancer, B-and T-cell acute lymphoblastic leukemias and acute myeloid leukemia) [2,3,[15][16][17]19,28]. In general, it has been demonstrated that the antitumor action mediated by L-733,060 is more potent than that exerted by aprepitant and that the antitumor action of aprepitant is more potent than that of L-732,138 [29].…”