Neurokinin-1 Receptor (NK-1R) Antagonists as a New Strategy to Overcome Cancer Resistance
Abstract
:Simple Summary
Abstract
1. Introduction
1.1. The Challenge of Drug-Resistant Tumors
1.2. Tachykinins
- The transcription of the TAC1 gene (NCBI Gene ID: 6863) produces the pre-protachykinin-A (PPTA)-mRNA, which is converted into one of four splice variants coding for a pro-tachykinin polypeptide that contains NK-1 [29], Neurokinin A (NKA, formerly known as substance K) and the NH2-terminally extended forms of NAK neuropeptide K (NPK) and neuropeptide gamma (NPγ) [22,26,30]. These peptides function as neurotransmitters by interacting with nerve receptors and smooth muscle cells [30].
- TAC3 (NCBI Gene ID: 6866) encodes a preprotein that is further cleaved to generate a mature secreted neuropeptide (neurokinin B, NKB). NKB is primarily expressed in the central and peripheral nervous systems and functions as a neurotransmitter [31]. NKB is a critical central regulator of gonadal function and its alterations are mainly associated with hypogonadotropic hypogonadism [32].
- Finally, TAC4 (NCBI Gene ID: 255061) produces endokinins (EK) A, A/B, C and D as well as hemokinins [12,28], which are associated with the hematopoietic system and lymphocyte B maturation [12]. TAC4 gene products are thought to regulate different peripheral endocrine and paracrine functions, including blood pressure, the immune system and endocrine gland secretion [33].
1.3. Tachykinins and Tachykinin Receptors in Human Disease and as Pharmacological Targets
1.3.1. Tachykinins and Tachykinin Receptors in Human Disease
- Respiratory disorders
- Smooth muscle disfunction:
- Central nervous system disorders:
- Hormonal disorders:
1.3.2. Marketed Tachykinin Receptor Antagonists
1.3.3. Aprepitant as Candidate for Drug Repurposing
2. Substance P/Neurokinin-1 System as a Target for Cancer Treatment
2.1. NK-1 Receptor
2.2. NK-1 Receptor Signaling Pathways with a Role in Cancer
2.3. Targeting NK-1R/SP Axis to Overcome Tumor Resistance
2.4. Preclinical Research
2.5. Clinical Research
3. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Gene | Tachykinin | Sequence | Preferred Tachykinin Receptor |
---|---|---|---|
TAC1 | Neurokinin 1 (NK1),Substance P (SP) | RPKPQQFFGLM [26] | Neurokinin 1 receptor (NK-1R) |
Neurokinin A (NKA) Substance K (SK) | HKTDSFVGLM [26] | Neurokinin 2 receptor (NK-2R) | |
Neuropeptide K (NPK) | DADSSIEKQVALLKALYGHGQISHKRHKTDSFVGLM [26] | Neurokinin 2 receptor (NK-2R) | |
Neuropeptide γ (NP γ) | MKILVALAVFFLVSTQLFAEEIGANDDLNYWSDWYDSDQIKEELPEPFEHLLQRARRPKPQQFFGLMGKRDADSSIEKQVALLKALYGHGQISHKRHKTDSFVGLMGKRALNSVAYERSAMQNYERRR (1st part)GHGQISHKRHKTDSFVGLM (2nd part) [26] | Neurokinin 2 receptor (NK-2R) | |
TAC3 | Neurokinin B (NKB)Neuromedin-K | DMHDFFVGLM [27] | Neurokinin 3 receptor (NK-3R) |
TAC4 | Endokinin A (EKA) | DGGEEQTLSTEAETWVIVALEEGAGPSIQLQLQEVKTGKASQFFGLM [28] | Neurokinin 1 receptor (NK-1R) |
Endokinin A/B (EKA/B) | GKASQFFGLM [28] | Neurokinin 1 receptor (NK-1R) | |
Endokinin C (EKC) | KKAYQLEHTFQGLL [28] | Neurokinin 1 receptor (NK-1R) | |
Endokinin D (EKD) | VGAYQLEHTFQGLL | Neurokinin 1 receptor (NK-1R) |
Cancer Type | Relevant Results |
---|---|
Breast |
|
Colon cancer |
|
Cervical cancer |
|
Melanoma |
|
Lung cancer, Urinary bladder carcinoma |
|
Lung cancer |
|
Prostate cancer |
|
Glioblastoma |
|
Chronic and acute myeloid leukemia |
|
Rhabdoid tumors |
|
Human pancreatic ductal adenocarcinoma |
|
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Share and Cite
García-Aranda, M.; Téllez, T.; McKenna, L.; Redondo, M. Neurokinin-1 Receptor (NK-1R) Antagonists as a New Strategy to Overcome Cancer Resistance. Cancers 2022, 14, 2255. https://doi.org/10.3390/cancers14092255
García-Aranda M, Téllez T, McKenna L, Redondo M. Neurokinin-1 Receptor (NK-1R) Antagonists as a New Strategy to Overcome Cancer Resistance. Cancers. 2022; 14(9):2255. https://doi.org/10.3390/cancers14092255
Chicago/Turabian StyleGarcía-Aranda, Marilina, Teresa Téllez, Lauraine McKenna, and Maximino Redondo. 2022. "Neurokinin-1 Receptor (NK-1R) Antagonists as a New Strategy to Overcome Cancer Resistance" Cancers 14, no. 9: 2255. https://doi.org/10.3390/cancers14092255