ReviewTargeting Ca2+ signalling through phytomolecules to combat cancer
Graphical abstract
Hypothetical modulations of altered calcium channels/pumps by using phytomolecules in cancer cells.
Introduction
Globally, cancer is amongst the leading cause of death and is liable for approximately 9.6 million deaths in 2018. About 1 in 6 deaths is because of cancer, and almost one-third of deaths caused by cancer are due to common risks factors such as low fruit and vegetable intake, high body mass index, lack of physical activity, alcohol and tobacco [National Cancer Control Programme, WHO, 2002]. Additionally, anticancer drug resistance, reoccurrence of the tumor after surgery, lack of effective medication/therapy and a higher degree of side-effects are the major issues to tackle in the field of cancer research [1]. Therefore, the need for designing effective drugs for the treatment, identifying new targets and new methods for targeted drug delivery systems are never-ending. In the recent past, Ca2+ signalling toolkits, which are modulated in cancerous cells, are emerging as a new target to cure cancer [2]. The major causes for the deregulation of Ca2+ homeostasis in cancer cells are contributed by the remodelling of the particular Ca2+ ion transporters or pumps expression. Most of the cases depict changes in the expression of different Ca2+ ion channels might be specific for certain cancer sub-types. Most of the studies assessing Ca2+ signalling in cancer have focused on findings modulation in the expression levels of specific Ca2+ ion-permeable channels. During carcinogenesis, in few cancer cells, Ca2+ signalling is considerably modulated compromising usual physiological functions, along with enabling them to compete with normal cells by providing unlimited advantages for uncontrolled multiplication, apoptosis resistance, the formation of new blood vessels and nutrients sparse conditions, invasion and distribution away from the initial tumor site [3]. In addition to learning the receptors/pumps or channels involved in Ca2+ signalling that are remodelled differently at various stages of cancers such as progression, proliferation & metastasis which is still a novel area of research, there is always a constant need to explore new potential drug candidates or design new drugs candidates. Recent literature proposes that plants are a good resource to provide phytochemicals which may be useful in combating cancer by targeting modulated Ca2+ signalling toolkit. Several plants containing active molecules have been identified to suppress the progression and development of tumors. These phytomolecules selectively limits rapidly dividing cells, inhibit angiogenesis and induce apoptosis by targeting abnormally expressed molecular factors or cell growth factors or producing cytotoxicity in cancerous tissue [4]. For example, some flavonoids (e.g., alpinum isoflavone and methoxylicoflavanone), polyphenols (e.g., gallocatechins and resveratrol), and steroids (e.g., epibrassinolid and homocatasterone) induce apoptosis in cancer cells.
Similarly, other phytomolecules such as rutin, allicin, gingerol, β-carotene, quercetin, thymol, curcumin, and rosmarinic acid produce anticancer effects through antioxidant mechanisms. Some of them are well known to produce cytotoxicity effects, e.g., vinblastine, vincristine, elliptinium, etoposide, 10-hydroxycamptothecin, colchicinamide, curcumol, gossypol, ipomeanol, taxol, lycobetaine, tetrandrine, monocrotaline, curdione, and indirubin [5]. All such phytomolecules produce their pharmacological effects by hindering different biochemical signalling and pathways such as the LKB1-AMP kinase (AMPK) and PI3 kinase (PI3K) pathway [6]. Although, these studies do not reflect the potential of the phytomolecules in the context of cancer treatment by targeting specific Ca2+ ion-permeable channels/pumps, however, the opportunities of repurposing the potential of phytomolecules in targeting specific Ca2+ channels/pumps in cancer cells may be explored in future. In this review, an overview of Ca2+ signalling and how it is remodelling in cancer cell promotes the survival of cancer cells is being discussed. Additionally, various phytomolecules which have been reported to specifically blocks or regulates Ca2+ channels/pumps has been enlisted, in the context of their potential application to the targeted cancer cells. Furthermore, latest strategies have also been highlighted which could be applied in targeting cancer cells using plant-based molecules.
Section snippets
An overview of Ca2+ signalling
Ca2+ is an intracellular messenger regulates a diverse range of physiological and biochemical functions by activation or inhibition of various cellular signals. The produced signals are specifically organised and control a wide variety of complex cellular events such as cell apoptosis, proliferation, cell contraction, exocytosis, fluid secretion, and gene transcription in all kind of cells [7]. Ca2+ signals follow complex temporal and spatial arrangements inside the cells. The resting free
Ca2+ channels associated phytomolecules with anticancer activity
Since last many years chemotherapeutics have been potentially used for the treatment of various cancers, but their non-specificity leads to adverse side effects and tissue toxicity. Conversely, phytochemicals possess high safety profile because of their antioxidant, and low toxicity nature increasing their general acceptance to be investigated for the prevention of cancer. These molecules are natural, and most of them are extensively present as dietary food components. These molecules target
Challenges and strategies to target Ca2+ channels using phytomolecules
Natural products have been used as herbal medicines since the dawn of human evolution. Today, about one-third of the top-selling pharmaceuticals are either pure phytopharmaceuticals or its derivatives. Although many of the drugs used today are isolated from natural products, still major pharmaceutical companies have not paid due attention to these compounds. One of the biggest issues with the use of natural products for treatment is its low bioavailability. In-spite of consisting extraordinary
Conclusion and future aspects
In the recent past, it has become evident that specific Ca2+ signalling channels/pumps are associated with the survival of a wide range of cancers cells. The modulation in the Ca2+ signalling toolkit is vital for the proliferation, metastasis and apoptotic resistance of the cancer cells. Recently identified Ca2+ transporters and channels belonging to TRP super-family, naturally grab the attention of the scientific community, resulting in numerous reports on the Ca2+ channel proteins involved in
Conflict of interest
The author (s) confirms that this article content has no conflict of interest.
Acknowledgments
We are grateful to the Director, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow for rendering essential facilities required for the experimental work and also acknowledges, SERB-DST, New Delhi (EEQ/2016/000121 (Ver-1)), CSIR-Aroma Mission Project (HCP-007) and CSIR-Phytopharma Mission Project (HCP-010) for financial support. JS acquiesce Council of Scientific and Industrial Research, New Delhi forJunior Research Fellowship.
References (202)
- et al.
Environment, cancer and inequalities-The urgent need for prevention
Eur. J. Cancer
(2018) - et al.
Calcium signaling and the therapeutic targeting of cancer cells
Biochim. Biophys. Acta Mol. Cell Res.
(2018) - et al.
Calcium signaling and cell cycle: progression or death
Cell Calcium
(2018) - et al.
Phytoestrogens and breast cancer: in vitro anticancer activities of isoflavones, lignans, coumestans, stilbenes and their analogs and derivatives
Biomed. Pharmacother.
(2018) - et al.
Plant derived anticancer agents: a green approach towards skin cancers
Biomed. Pharmacother.
(2018) Inositol trisphosphate and calcium signalling mechanisms
Biochim. Biophys. Acta
(2009)- et al.
Calcium signalling-an overview
Semin. Cell Dev. Biol.
(2001) - et al.
Why calcium? How calcium became the best communicator
J. Biol. Chem.
(2016) - et al.
Uncoupling cell shrinkage from apoptosis reveals that Na+ influx is required for volume loss during programmed cell death
J. Biol. Chem.
(2003) - et al.
Selective role of intracellular chloride in the regulation of the intrinsic but not extrinsic pathway of apoptosis in Jurkat T-cells
J. Biol. Chem.
(2006)
Plasma membrane calcium channels in cancer: alterations and consequences for cell proliferation and migration
Biochim. Biophys. Acta
Calcium channels and pumps in cancer: changes and consequences
J. Biol. Chem.
Ion channel expression as promising cancer biomarker
Biochim. Biophys. Acta
Cholesterol-induced activation of TRPM7 regulates cell proliferation, migration, and viability of human prostate cells
Biochim. Biophys. Acta
Store-independent activation of Orai1 by SPCA2 in mammary tumors
Cell
ORAI3 silencing alters cell proliferation and cell cycle progression via c-myc pathway in breast cancer cells
Biochim. Biophys. Acta
Ca(2+)-dependent stimulation of retinoblastoma gene product phosphorylation and p34cdc2 kinase activation in serum-stimulated human fibroblasts
J. Biol. Chem.
The ins and outs of RB: coupling gene expression to the cell cycle clock
Trends Cell Biol.
PI3-kinase promotes TRPV2 activity independently of channel translocation to the plasma membrane
Cell Calcium
TRPM7 triggers Ca2+ sparks and invadosome formation in neuroblastoma cells
Cell Calcium
Orai1 and STIM1 are critical for breast tumor cell migration and metastasis
Cancer Cell
Ca2+ homeostasis in apoptotic resistance of prostate cancer cells
Biochem. Biophys. Res. Commun.
Piperine, a dietary phytochemical, inhibits angiogenesis
J. Nutr. Biochem.
Lysophospholipids stimulate prostate cancer cell migration via TRPV2 channel activation
Biochim. Biophys. Acta
Arachidonyl ethanolamide induces apoptosis of uterine cervix cancer cells via aberrantly expressed vanilloid receptor-1
Gynecol. Oncol.
Evodiamine and rutaecarpine alkaloids as highly selective transient receptor potential vanilloid 1 agonists
Int. J. Biol. Macromol.
Menthol regulates TRPM8-independent processes in PC-3 prostate cancer cells
Biochim. Biophys. Acta
Prospects for prostate cancer imaging and therapy using high-affinity TRPM8 activators
Cell Calcium
Methyl syringate, a TRPA1 agonist represses hypoxia-induced cyclooxygenase-2 in lung cancer cells
Phytomedicine
Pre-clinical and clinical study of QC12, a water-soluble, pro-drug of quercetin
Ann. Oncol.
A phase I study of concurrent chemotherapy and thoracic radiotherapy with oral epigallocatechin-3-gallate protection in patients with locally advanced stage III non-small-cell lung cancer
Radiother. Oncol.
An open-label extension study to investigate the long-term safety and tolerability of THC/CBD oromucosal spray and oromucosal THC spray in patients with terminal cancer-related pain refractory to strong opioid analgesics
J. Pain Symptom Manage.
Assessment of DNA damage and repair in adults consuming allyl isothiocyanate or Brassica vegetables
J. Nutr. Biochem.
Lead phytochemicals for anticancer drug development
Front. Plant Sci.
Calcium signalling: dynamics, homeostasis and remodelling
Nat. Rev. Mol. Cell Biol.
Calcium signalling
Curr. Biol.
Fluorescent indicators for Ca2+ based on green fluorescent proteins and calmodulin
Tanpakushitsu Kakusan Koso
Ion channels and apoptosis in cancer
Philos. Trans. R. Soc. Lond., B, Biol. Sci.
Depolarization potentiates TRAIL-induced apoptosis in human melanoma cells: role for ATP-sensitive K+ channels and endoplasmic reticulum stress
Int. J. Oncol.
Inhibitors of mitochondrial Kv1.3 channels induce Bax/Bak-independent death of cancer cells
EMBO Mol. Med.
Induction of apoptosis in macrophages via Kv1.3 and Kv1.5 potassium channels
Curr. Med. Chem.
Treatment of human glioblastoma cells with the staurosporine derivative CGP 41251 inhibits CDC2 and CDK2 kinase activity and increases radiation sensitivity
Anticancer Res.
Differential role of IK and BK potassium channels as mediators of intrinsic and extrinsic apoptotic cell death
Am. J. Physiol. Cell Physiol.
Chloride channels as drug targets
Nat. Rev. Drug Discov.
Tyrosine kinase-dependent activation of a chloride channel in CD95-induced apoptosis in T lymphocytes
Proc. Natl. Acad. Sci. U. S. A.
Inhibition of calcium-activated chloride channel ANO1 suppresses proliferation and induces apoptosis of epithelium originated cancer cells
Oncotarget
The Ca (2+) -activated Cl (-) channel, ANO1 (TMEM16A), is a double-edged sword in cell proliferation and tumorigenesis
Cancer Med.
Cell cycle regulation by checkpoints
Methods Mol. Biol.
Calcium and cancer: targeting Ca2+ transport
Nat. Rev. Cancer
Blockade of T-type Ca(2+) channels inhibits human ovarian cancer cell proliferation
Cancer Invest.
Cited by (11)
A comprehensive review on phytochemistry, molecular pharmacology, clinical and translational outfit of Ocimum sanctum L
2022, South African Journal of BotanyOroxylin A reversed Fibronectin-induced glioma insensitivity to Temozolomide by suppressing IP<inf>3</inf>R1/AKT/β-catenin pathway
2020, Life SciencesCitation Excerpt :Indeed, overexpression of IP3R is observed in a wide variety of cancer types, and usually correlated with increased proliferation and migration [28]. Ca2+ regulates a diverse range of physiological and biochemical functions in cancer, including proliferation, metastasis, cell contraction and fluid secretion [29]. Remodeling of Ca2+ signaling has been reported in various cancer types, such as changes in the activity or expression level of Ca2+ channels and Ca2+ transporters [30,31].
Emerging role of phytochemicals in targeting predictive, prognostic, and diagnostic biomarkers of lung cancer
2020, Food and Chemical ToxicologyCitation Excerpt :The primary issue associated with the phytochemicals for its use in treatment is poor availability, high hydrophilicity, or less lipid solubility, which limits its membrane permeability (Singh et al., 2019). Also, the metabolizing phase I and phase II enzymes involved in hydrolysis, oxidation, and reduction carry out excessive metabolism that further enhances the rate of its excretion (Singh et al., 2019). For example, the required dose of curcumin orally administered in humans is 3.6g/day to obtain 11.1 nmol/L serum level as the lower dose is not detectable in the plasma (Fadus et al., 2017).
Exploration of selected monoterpenes as potential TRPC channel family modulator in lung cancer, an in-silico upshot
2023, Journal of Biomolecular Structure and Dynamics
- 1
These authors contributed equally.