I. Introduction Purpose and Objectives

The purpose of the present report is to review the interactive biologic activities between the TRP cation channels and the antimicrobial (AMP) peptides. Thus, the overall goal of this treatise is to present and propose new and novel cancer therapeutics and treatments utilizing this potential dual combination of TRPs and AMPs. Secondarily, the scope of this paper will encompass a discussion of the dual molecular interactions of TRPs and AMPs in light of their cell surface membrane phenomenon and subsequent cytoplasmic signal transductions and protein-to-protein interactions in cancer cells.

A) Historical: TRP Cation Channels

The Transient Receptor Potential channels (TRPs) function as chemical biosensors of natural, toxic, and physical stimuli in addition to serving multiple roles in cell and tissue growth regulation [1]. In the present treatise, the structures and functions of TRPs are first introduced and discussed regarding their participating roles in various physiological and pathological conditions. Secondarily, the introduction and added functions of the AMPs are likewise described in the course of addressing disease states and their employing therapeutic interventions in combination with TRPs. Thus, an understanding of the growth regulatory roles of TRP channel interactions together with AMPLs in cancers could possibly lead to improved preventions and treatment regimens for malignant diseases and associated benign growth disorders.

The existence, presence, and discovery of TRP channels were first proposed in 1969, the source having been identified as a mutant gene in fruit flies displaying a transient rather than a continuous response to increase bright light rays [2]. In 1975, Minke et al. named this receptor-like protein after an electrophysiologic light responsive phenotype [3]. The TRP gene was later cloned in 1989 by Montell & Li, at which time the protein-gene product was identified and localized as a transmembrane associated protein [4,5]. It was later discovered that TRPs are cell membrane bright light activated components that regulate the influx of Ca⁺⁺ and other cations into cells by serving as voltage-gated channels.

B) The TRP Cation Channel Family and Its Functions

The mammalian TRP channel family members have presently been classified into six TRP subfamilies based on both their amino acid sequences and their topological membranous structure traits. The TRP channel family includes the following subtype members: 1) Canonical (TRPC); 2) melastatin (TRPM); 3) vanilloid (TRPV); 4) ankyrin (TRPA); 5) polycystic (TRPP); and 6) mucolipin (TRPL) channels [5]. All TRP subfamily channel members play essential roles in cation flow transduction in the influx and transfer of monovalent and divalent ions such as Na⁺, Mg⁺⁺, Mn⁺⁺, and Ca⁺⁺ into cells. These TRP channels regulate transduction flux pathways for a variety of sensory perceptions encompassing taste, pungent compounds, thermo-mechanical, pain, temperature, osmoregulation, and hormone/pheromone influx [20-23]. In addition to the TRP’s role in sensory perception, TRP channels can further mediate certain physiological, pathological, and functional roles in both cancer and immune system activities [6-9]. Thus, TRP channels can contribute to cancer pathologies and modulate growth activities via intracellular cation (especially Ca⁺⁺) elevations and oscillations; such activities can affect cell growth cycle functions, cell spreading and migrations, receptor crosstalk and signaling, and the initiation of programmed cell death (apoptosis) activities.

C) TRP Subfamilies Structural Topology

All mammalian TRP channels share common topological transmembrane (TM) peptide stretches that transverse the cell membrane six times comprising the formation of intramembranous segment loops. All TRP channels also display a spiral pore-forming loop between transmembrane segments 5 and 6 in which the amino acid sequence contents are highly conserved among family members which function to coordinate cation influx activities [14]. Overall, the TM diverse domains and motifs have been found to include and consist of coiled coils, calmodulin binding sites, lipid interaction domains, EF hands, and phosphorylation sites. Nonetheless, the individual and precise structural motifs and domains can slightly vary within the individual class members of the TRP subfamilies [13]. Furthermore, there appears to be few cancer-induced gene mutations in the TRP families. Moreover, these changes can include various increases in the genetic expression of the TRP channels, especially in the TRPC, TRPM, and TRPV subfamilies [15].

D) The TRP Channels in Signal Transduction Pathways

The TRP channel have been localized to the cell surface membrane within the lipid bilayer in juxtaposition to a cluster of eight signal activating protein members collectively called the “Signalplex” unit. This signaling protein cluster unit is located at the point of membrane insertion where the TRP channels enter into the cell membrane and cluster together within the signalplex unit into the surface cell bilayer membrane [18]. This signalplex cluster composing eight signal proteins consist of an array of scaffolding and targeting proteins clumped in conjunction to form the signal complex together with the TRP channel; hence, the total signal proteins (8 +1) make up the molecular cluster nine proteins in the signalplex structure [19]. Thus, the nine signaling proteins of the signalplex are comprised of the following members: 1) the TRP channel itself; 2) Beta phospholipase-C; 3) Rhodopsin; 4) Protein kinase-C; 5) calmodulin; 6) myosin; 7) Beta-2-adrenergic receptor; 8) Na⁺H⁺ transporter; and 9) the Ezrin-Radin-moesin tricomplex unit [20].

II. Comparison of Characteristics and Traits of the Antimicrobial Peptides that Interact with the TRP Channels

The antimicrobial peptides (AMPs) are a class of broad-spectrum antibiotic agents that comprise various protein/peptide members of the innate host defense immune system present in many vertebrate animal species [21]. Different AMPs are widely found and distributed among fish, amphibians, reptiles, birds, and mammals including man [22]. In recent years, the AMPs have been found to function as additional adjunct compounds that aid in anti-cancer therapeutics. These therapeutic actions are accomplished via the AMPs homing in and onto cancer cell surface membranes followed by their penetration into the cancer cell interior cytoplasm [23]. The AMPs owe their capability to penetrate into cancer cells to their ability to attach, lyse, destabilize, and disrupt bilayer membranes and forms pores. These AMP interactions with cancer cell biomembranes can be traced to their binding to the cell surface net negative charge on the cell membrane which is also found present on microorganisms (bacteria), cancer, and stem cells [24]. The AMPs, which can be produced from both synthetic and natural sources, demonstrate high targeting specificity toward and onto cancer cells but not onto normal, non-malignant body cells.

Mammals exhibit two major classes of AMPs, namely: 1) the cathelicidins, and 2) the defensins [25]. Both classes of AMPs demonstrate antibacterial and anti-tumor properties. However, it is only the defensins class of AMPs that have been found to occur in human beings. Both human alpha and beta defensins are produced and have been localized on body cells such as neutrophils, leucocytes, macrophages, and certain epithelial cells. Such cells can be found and localized in respiratory, digestive, and excretory systems [26,27]. In addition, AMPs have also been found on certain circulating vascular blood cells.

Even though the AMPs are commonly not associated with pregnancy, an AMP-like pregnancy peptide was discovered by the author (GJM) and published in 1996. This peptide is a pregnancy associated AMP-like (AMPL) peptide that has been named the Growth Inhibitory Peptide (GIP-34) [28]. The fetal GIP comprises a peptide derived as an intrinsic amino acid segment found buried and concealed within the Alpha-fetoprotein molecular folds and is present in mammalian pregnancies [29]. Interestingly, the AFP pregnancy-derived GIP peptide was found to have many properties in common and has been classified with the cationic β sheet AMPL-peptides being most similar to the human defensin family of peptides [30]. Both the GIP and the defensin class of peptides contain 2 to 8 cysteine residues forming at least one or more sets of disulfide bridges crucial for many biological functions. The defensin peptides, like GIP, also contain beta-hairpin loops, beta sheet formations, excess hydrophobic amino acids, and a short segment stretch of alpha-helical secondary structures [38]. Overall, the GIP peptide was found to share many of the above secondary structures in common with the AMPL-defensin peptides [31].

III. Interactions Already Known Between TRPs and AMP-Like Peptides

The calcium dependent TRP channels play multifunctional roles in cell growth, tumorigenesis, and cell growth cycle-associated functions. These calcium-associated cation channels function in determining cell membrane voltage, cytoplasmic Ca⁺⁺ concentrations, and receptor signaling mainly in proliferating cells [32]. As described above, the TRP channels are transmembrane cation channels similar in function with other voltage-gated Ca⁺⁺ channels (Table-2). The TRPs and similar ion channels are constitutively open and gated by voltage, ATP, pH, redox agents, and multiple sensory activation factors such as spices and phytochemicals (Table-1) [33]. As described above, the TRP channels act in concert with a cluster of eight other protein members that make-up the signalplex cluster for receptor signaling purposes. These proteins can be summarily described as phosphatases, kinases, co-transporters, receptors, and cytoskeletal-like proteins [18-20]. The TRP channels normally function in the regulatory activities of the Ca⁺⁺ and other cation influx into the cytoplasmic interior and further participate in activities regarding cancer growth and proliferation (Table-2). However, excessive and non-regulated Ca⁺⁺ influx into the cell can result in dysfunctional receptor signaling and gene transcription, faulty DNA repair, and ultimately in apoptotic- induced cell death [35] (see below).

Table 1

Table 2

The expression patterns of TRPs in cancer cells (i.e., breast cancer) revealed that certain TRP channels (namely TRPV1 and TRPM8) were heavily over-expressed in various breast cancer cell types including glandular, ductal, basal, and interstitial (fibrous) cells [36]. Hence, it is of further interest that the use of an in-silica computer allosteric docking/binding program used for GIP (see technical endnotes below) revealed that GIP was capable of binding (docking) with TRP channels and cell growth cycle proteins (Table-3). Two activating sensory factors (spices) involved in allowing high Ca⁺⁺ influx into the breast cancer cells were identified first as capsaicin and secondly as peppermint oil (menthol), among other spices [36-39] (Table-1). It is of interest that recent reports indicated that the aforementioned GIP was capable of interacting with the TRPM and TRPV subfamilies of TRP channels among others [40-45]. These latter data have been verified by electrophysiological (EP) procedures employing sharps electrode and patch clamp methodologies using micro-manipulated electrode probes inserted into cultured breast cancer cells [37,38]. Since those reports emerged, additional activation factors (spices) for TRPs have been described in such cancers as lungs, colon, prostate, pancreas, brain, and urinary bladder tumors (Table-1) [39, 40-45].

The electrophysiologic (EP) based methodologies revealed that the previously mentioned phytochemical (spice) activated channels treated with 10mmol GIP peptide functioned to increase the influx of Ca⁺⁺ ions into the cancer cells while increasing the membrane potential of the cultured breast cancer cells [8,38]. This increase, in turn, immobilized the current membrane potential which extended across a range of -30-to-45 mVolts persisting for a 90-minute time duration [45]. Additional studies using the EP methods against LNCAP prostate cancer cultured cells confirmed that the GIP peptide results reported in the breast cancer cell studies were further confirmed in prostate cells [7,36]. Upon measurements of the slope conductance, the GIP peptide treatments demonstrated a substantial membrane current increase (with decreased resistance) in both cancer cell studies. Thus, the data in two different cancer cell types demonstrated and confirmed that the membrane potential and resistance effects exemplified by the highly enhanced (increased) Ca⁺⁺ influx had affected the cytoplasmic Ca⁺⁺ stores. Such organelle storage compartments occur in the mitochondria and secondarily in the Ca⁺⁺ stores of the endoplasmic reticulum. This 2-stage storage activity, reflecting the overload of Ca⁺⁺ ions in two organelles, initiated the process of apoptotic cell death observed in both the cultured breast and in the prostate, cancer cells [36,45].

As described above, it has also been reported that the AFP-derived GIP can act as a sensor agonist to TRP channels in the course of enhancing phase interactions that can inhibit the cell growth cycle of cancer cells [37,38]. Thus, the TRP channel activation and subsequent interactions with AMPLs can directly affect various stage phases of the cell growth cycle [8]. Cells in the cell cycle G1 phase have been reported to display depolarized membrane potentials corresponding to a large contact engagement with the TRP channel current. The use of cultured breast cancer cells involved a millivolt range known to represent the cation channel that corresponds to and regulates the G1 phase of the cell cycle [38]. Thus, an increased hyper-polarization current occurs that corresponds to an increased intensity of a cation induced TRP membrane current that occurred in the phases in the cell growth cycle [8].

Table 3

Table 4

In order to more fully understand the functional effects of the GIP-34 interaction with TRPs in the cell growth suppression of breast cancer cells, a global RNA microarray assay was subsequently performed (Table-4). It was subsequently demonstrated that GIP affected the RNA outcome analysis by altering the RNA expression transcripts of 716 proteins after 8 days of GIP peptide treatment in the breast cancer cell cultures. A total of 431 RNA transcripts were down-regulated, while 286 transcripts were up-regulated. Some of the RNA transcript for proteins involved cell growth examples in which eleven transcripts were down-regulated in cell growth cycle associated proteins that included Cyclic-E, SKP2, and checkpoint suppressor-1 (CHES1) proteins (Table-4). Other RNA transcripts in table-4 included cell cycle-associated proteins such as the ubiquitin protein degradation system which included the SUMO/Sentrin/SMT3, protease-49, and the ubiquitin ligase system. The third group of RNA transcripts that were down-regulated included the apoptosis associated (cell death) proteins (Table-4) [51,52].

IV. Concluding Remarks

The present treatise has demonstrated that certain members of the TRP family of cation channels are over-expressed in various breast and other cancer cell types [7,8]. Over-expression can serve both as an aid, a benefit and an advantage in cancer therapy studies. This is due to the fact that many more TRP channels are involved in breast cancer cells compared to normal cells. Thus, the over-expressed TRP channels in cancer cells compared to those of non-malignant cells indicate that overly excessive amounts of Ca⁺⁺ ions undergo unrestricted influx passage of Ca⁺⁺ into the cancer cell cytoplasm. An unregulated highly excessive influx of Ca⁺⁺ ions into the TRP channel can ultimately result in destroying the cancer cell by allowing excess Ca⁺⁺ cation overflow into 1) the mitochondria Ca⁺⁺reserve and 2) the endoplasmic reticulum Ca⁺⁺ reserve compartments. These two successive compartmental overflow events can cause result in cell death via a programmed cell death process (i.e., apoptosis) initiated by the cancer cell. Thus, it can easily be ascertained that cell death by apoptosis is not due to the direct GIP action of opened TRP channels, but rather to the excessive influx of Ca⁺⁺ into the two cancer cytoplasmic reserve organelles. This is because GIP only functions to keep the Ca⁺⁺ channel opened for a protracted time period. Instead, cell death can be solely attributed to the uncontrolled, unrestrictive and dysregulated excessive flow of Ca⁺⁺ cations into the cell cytoplasm. This overflow enters into the MT and ER reserve chambers/compartments. These two overflow action of Ca⁺⁺ ions into the mitochondria and endoplasmic reticulum, then triggers a program of cell death induction process of apoptosis within the cancer cells [46-49].

Postscript Notes

It should be noted and clarified that the molecular pathways and electrophysiologic mechanisms of action in the present report have not yet been fully elucidated at the present time. These molecular pathways and mechanisms are presently under study and have not yet been adequately explained and understood. Such events which are under further research study include: 1) the cell surface membrane electrical charge phenomenon on the cancer cell membrane. This event is in regard to the nature of the ionic medium in which the cells are found, and the valence of the ions found therein; 2) the measure of the Zeta potential of the electrical charge on the cell surface membrane in a liquid phase; 3) the linear current events regarding the inward and outward rectification current changes under defined test conditions; and 4) cell membrane measurements of the electrical currents, voltage, amperage, and resistance simultaneously taking place. These electrical physiological measurements in the above situations presently need further research study and have yet to be resolved or published to date [54,55].

Declarations and Acknowledgements

Funding

None; no US federal grants were used in the preparation of this paper.

Conflicts of Interest

The author declares there are no known conflicts of interest used in the preparation of this manuscript.

Acknowledgements

The author extends his thanks and gratitude to Ms. Sarah Andres for her commitment and time expenditure in the skilled typing and processing of the manuscript, references, and tables of this report. The author also acknowledges the Serometrix LLC Biotech company, Pittsford NY for the use of their drug discovery computer software platform (see Table-4).

Technical Notes Addendum

Computer Supporting Data: An “in silica” search for pairing of peptide-to-protein Interactions:

“The Peptimer Discovery Program.” AFP and its derived peptides are bristling with matching short amino acid segment sites matched to cytokines, chemokines, and immune system amino acid sequence identities which are located throughout the AFP polypeptide molecule. The protein-to-peptide amino acid pairing computer software program (peptimer) from Serometrix Biotech Company (Syracuse, NY) revealed that the GIP peptide contained multiple matched allosteric amino acid pairing interaction sites with cellular and cancer-associated proteins. Such protein sites (amino acid segments) can forecast potential targets for future therapeutic approaches for cancer therapies treatments (50). Such amino acid pairing interactions could affect signal transduction pathways by inhibiting (or enhancing) receptor binding by blocking protein-to-peptide interactions (53). As shown in Table-3, the matched interacting sites with GIP included: 1) growth factors; 2) cell cycle proteins; 3) ubiquitins; 4) apoptosis associated proteins; 5) calcium-linked proteins; and 6) TRP channel proteins. Matched detection of these pinpointed target interactions of cell growth cycle proteins might cause cancers to regress to less severe and reduce patient symptoms. Therefore, preventing such interactions in cancer patients could lead to new treatments and improved cancer and modalities in clinical patients.

References

1. Zhang M, Ma Y, Ye X, Zhang N, Pan Z, Wang B (2023) TRP (transient receptor potential) ion channel family: structures, biological functions and therapeutic interventions for diseases. Signal transduction and targeted therapy, 8: 261-73.
2. Montell C (2005) TRP channels in Drosophila photoreceptor cells. J. Physiol., 567: 45-51.
3. Minke B, Cook B (2002) TRP channels proteins and signal transduction. Physiol Res, 10: 1152- 72.
4. Li H, Montell C (2000) TRP and the PDZ protein, Inad, form the core complex required for retention of the signalplex in Drosophila photoreceptor cells. J Cell Biol, 150: 1411-22.
5. Nishida M, Hata Y, Yoshida T, Inoue R, Mori Y (2006) TRP channels: molecular diversity and physiological function. Microcirculation, 13: 535-50.
6. Ferrer-Monteil A, Fernandez-Carvajal A, Planells-Cases R et al. (2012) Advances in modulating thermosensory TRP channels. Expert Opin Pat, 22: 999-1017.
7. Skryma R, Mariot P, Bourhis XL, Coppenolle FV, Shuba Y, et al. (2006) Calcium currents in LNCaP cells. J. Physiol. 527: 71-83.
8. Wonderlin WF, Woodfork KA, Strobl JS (1995) Changes in membrane potential during the progression of MCF-7 human mammary tumor cells through the cell cycle. 165: 177-85.
9. Marini M, Titiz M, Monteiro de Araujo DS, Geppetti P (2022) TRP channels in cancer: signaling mechanisms and translational approaches. Biomolecules, 13: 1557-67.
10. Zhivotosky B orrenius (2011) Calcium and cell death mechanisms: A perspective from the cell death community. Cell calcium, 50: 211-21.
11. Verkhrastsky A (2007) Calcium and cell death. Subcell BIochem, 45: 465-80.
12. Thompson CB (1995) Apoptosis in the pathogenesis and treatment of disease. Science., 267: 1456-62.
13. Kalia J, Swartz KJ (2013) Exploring structure-function relationships between TRP and Kv channels. Sci Reports, 3: 1523-6.
14. Clapham DE, Runnels LW, Strubing C (2001) The TRP ion channel family. Nat Rev Neurosci. 2: 387-96.
15. Guo H, Carlson JA, Slominski A (2012) Role of TRPM in melanocytes and melanoma. Expl Dermatol. 21: 650-4.
16. Beech DJ (2012) Integration of transient receptor potential canonical channels with lipids. Acta Physiol (Oxf). 204: 227-37.
17. Xu S, Zhang L, Cheng X, Yu H, Bao J, Lu R (2018) Capsaicin inhibits the metastasis of human papillary thyroid carcinoma BCPAP cells through the modulation of TRPV1 channel. Food Funct. 9: 344-54.
18. Redondo P, Rosado J (2015) Store-operated calcium entry: unveiling the calcium handling signalplex. Intl Rev Cell Mol, 316: 183-226.
19. Zasshi NY (2003) TRP channels: formation of signal formation of signal complex and regulation of cellular functions. Nihon Yakurigaki. 121: 223-32.
20. Goel M, Sinkins Q, Keightley A, Kinter M, Schilling W (2005) Proteomic analysis of TRPC5- and TRPC6 binding partners reveals interaction with the plasmalemmal Na (+)/K(+) ATPase. Pflugers Arch, 451: 87-98.
21. Pasupuleti M, Schmidtchen A, Malmsten M (2012) Antimicrobial peptides: key components of the innate immune system. Crit Rev Biotechnol. 32: 143-71.
22. Lee HT, Lee CC, Yang JR, Lai JZC, Chang KY (2015) Large scale structural classification of antimicrobial peptides. Biomed Res Int. 2015: 1-6.
23. Arasre F, Abnous K, Hashemi M, Taghdisi SM, Ramezanni M, et al. (2018) Peptide-based targeted therapeutics: focus on cancer treatment. J. Control Release. 292: 141-62.
24. Wang CK, Shih LY, Chang KY (2017) Large sclae analysis of antimicrobial activities in relation to amphipathicity and electrical charge reveals novel characterizations of antimicrobial peptides. Molecules. 22: 32-40.
25. Van Harten RM, Van Woundenbergh E, Van Dijk A, Haagsman HP (2018) Cathelicidins: Immunomodulatory antimicrobials. Vaccines (Basel). 6: 63.
26. Yang D, Biragyn A, Kwak LW, Oppenheim JJ (2002) Mammalisn defensin in immunity: more than just microbicidal. Trends Immunol. 23: 291-6.
27. Fruitwala S, El-Naccache DW, Chang TL (2019) Multifacetedd immune functions of human defensins and underlying mechanisms. Semin Cell Dev Biol. 88: 163-72.
28. Mizejewski GJ, Dias JA, Hauer CR, Henrikson KP, Gierthy J (1996) Alpha-fetoprotein derived synthetic peptides: assay of an estrogen-modifying regulatory segment. Mol. Cell Endocrinol. 118: 15-23.
29. Mizejewski GJ (2004) Biological roles of alpha-fetoprotein during pregnancy and perinatal development. Exp Biol. Med (Maywood). 229: 439-63.
30. Kluver E, Schulz-Maronde S, Scheid D, Meyer B, Forssman WG et al. (2005) Structure-activity relations of human beta-defensin 3: influence of disulfide bonds and cysteine substitutions on antimicrobial activity and cytotoxicity. Biochemistry. 44: 9804-16.
31. Contreras G, Shirsel I, Braun MS, Wink M (2020) Defensins: transcriptional regulations and functions beyond antimicrobial activity. Dev comp Immunol. 104: 103556-63.
32. Avila EE (2017) Functions and antimicrobial peptides in vertebrates. Curr Protein Pept Sci. 18: 1098-119.
33. Mizejewski GJ (2017) Breast cancer and transient receptor potential (TRP) cation channels; Is there a role for non-selective TRP channels as therapeutic cancer targets? A commentary. Intl. J. Can. Res. And develop. 2: 4-7.
34. Berridge MJ, Bootman MD, Roderick HL (2003) Calcium signaling dynamics, homeostasis, and remodeling. Nat Rev Mol Cell Biol. 4: 517-29.
35. Orrenuis S, Goguadze V, Zhivotosku B (2015) Calcium and mitochondria in the regulation of cell death. BIochem Biophys Res Commun. 460: 72-81.
36. Weber L, Al-Refae K, Wolk G, Bonatz G, Altmuller J, Becker C, Giesselmann G, Hatt H (2016) Expression and functionality of TRV1 in breast cancer cells. Breast Cancer. Targets and Therapy 8: 243-8.
37. Woodfork KA, Wonderlin WF, Peterson VA, Strobl JS (1995) Inhibition of ATP-sensitive potassium channels causes reversible cell-cycle arrest of human breast cancer cells in tissue culture. J cell Physiol. 162: 163-71.
38. Wonderlin WF, Woodfork KA, Strobl JS (1995) Changes in membrane potential during the progression of MCF-7 human mammary tumor cells through the cell cycle. J Cell Physiol. 165: 177-85.
39. Legrand C, Merlini JM, de Denarciens-Bezencom C (2020) New natural agonists of the transient receptor potential Ankyrin 1 (TRPA1) channel. Scitif Reprots. 10: 11238-41.
40. Ahmed AG, Hussein UK, Ahmed AE, Kim KM, Mahmoud HM, Hammouda O, Jang KY (2020) Mustard seed (Brassica nigra) extracts exhibit antiproliferative effect against human lung cancer cells through differential regulation of apoptosis, cell cycle, migration and invasion. Molecules, 25: 2069-76.
41. Nachvak SM, Soleimani D, Rahimi M, Azizi A, Moradinazar M, Rouani MH, Halashi B (2022) Ginger as an anti-colorectal cancer spice: A systematic review of in vitro to clinical evidence. Food Sci Nutr; 11: 651-60.
42. Wissenbach U, Niemeyer BA, Fixemer t, Chneidewind A, Trost C, Cavalie A, Reus K, Meese E, Bonkhoff H, Flockerzi V (2001) Expression of CaT-like, a novel calcium selective channel correlates with the malignancy of prostate cancer. J. Biol Chem, 76: 19461-8.
43. Giangaspero F, Santoni G (2007) Capsaicin-induced apoptosis of glioma cells is mediated by TRPV1 vanilloid receptor and requires p38 MAPK activation. J Neurochem. 102: 977-90.
44. Mistretta F, Buffi NM, Lughezzani G, Lista G, Larcher A, Fossati N, Abrate A, Dell-Oglio P, Montorsi F, Guazzoni G, Lazzeri M (2014) Bladder cancer and urothelial impairment: the role of TRPV1 as potential drug target. Biomed Res Int 2014: 987149.
45. Mizejewski GJ (2024) Unveiling the relationships of calcium ions, transient receptor potential channels, and fetal peptides with calcium induced fetal death. Recent trends in can. Res. 1: 1-9.
46. Galluzzi L, Vitale I, Aaronson SA, et al. (2018) Molecular mechanisms of cell death: recommendations of the Nomenclate Committee on cell death. Cell Death Differ, 25: 486-541.
47. Orrenius S, Goguadze V, Zhivotosky B (2015) Calcium and mitochondria in the regulation of cell deaths. Biochem. Biophy. Res. Commun. 460: 72-81.
48. Ji C, Zhang Z, Li z, She X, Wang X, Li B, Xu X, Song , Zhang D (2002) Mitochondria-associated endoplasmic reticulum membranes: inextricable linked with the autophagy process. Oxidative Med. Cell Langev, 2022: 7086807
49. Zhou X, Hao W, Shi H, How Y, Xu Q (2015) Calcium homeostasis disruption—a bridge connecting cadmium-induced apoptosis, autophagy and tumorigenesis. Oncol Res. Treat, 38: 310-5.
50. Mizejewski G (2016) The third domain fragment of alpha-fetoprotein (AFP):Mapping AFP interaction sites with selective and non-selective cation channels. Curr Topics in Peptide and Protein Research. 16: 63-82.
51. Mizejewski GJ (2011) Mechanisms of cancer growth suppression of alpha-fetoprotein derived growth inhibitory peptides (GIP): Comparison of GIP-34 versus GIP-8 (AFPep). Updates and Prospects. Cancers, 3: 2709-33.
52. Mizejewski GJ (2007) The alpha-fetoprotein derived growth inhibitory 8-mer fragment: review of a novel anticancer agent. Cancer biotherapy & radiopharmaceuticals, 22: 73-98.
53. Root-Berstein R (1982) Amino acid pairing. Journal of Theoretical Biology, 94: 885-94.
54. Zhang Y, Yang M, Pporteny N, Gui D (2008) Zeta potential: a surface electrical characteristic to probe the interaction of nanoparticle with normal and cancer human breast epithelial cells. Biomed. Microdevices, 10: 321-8.
55. Baca, JAM, Ortega AO, Jimeng AA, Principal SG (2022) Cell electrical charge analyses define specific properties for cancer cell activity. Biochem, 144: 108028-37.