Just another perspective: A Calcium perspective

It is well know that Ca, Na, K, Mg are some of the basic elements sitting at the base of the cell function. While looking at various anti cancer elements I realize that one perspective that may group anti cancer into two major categories is their impact on the intra cellular Ca. While the level of intra cellular cancer is very important some research papers show that the increase of intracellular Ca can lead to cancer progression while others show that this leads to the cancer cell death. I have to understand more in what conditions one or the other may happen, but for now I will start to group the well known anti cancer elements into the two major categories. This helps to have in mind when designing anti cancer treatment strategies as it may be highly relevant. Here are the two clusters:

1. Increasing Intracellular Calcium

Oleandrin: Additionally, oleandrin raises the intracellular calcium level, releases cytochrome C from mitochondria, and induces apoptosis through a caspase-dependent pathway. http://www.tbyil.com/autophagy.htm

Salinomycin: Selectively bind certain ions creating intra- and extracellular biochemical disturbances. The ions bound vary with different members of this class of drug, with salinomycin preferentially binding potassium. This interferes with potassium transport across mitchondrial membranes, resulting in low intracellular energy production. The Na+/Ca2+ exchange mechanism may also be disrupted allowing a fatal accumulation of intracellular calcium.1 This mechanism particularly affects skeletal muscle in all animals, and cardiac muscle in a few (eg, cattle).

Baicalein: induced apoptosis via endoplasmic reticulum (ER) stress, possibly by downregulating prosurvival Bcl-2 family, increasing intracellular calcium, and activating JNK. CHOP was the executor of cell death during baicalein-induced ER stress while eIF2 α and IRE1 α played protective roles. Protective autophagy was also triggered by baicalein in HCC cells. http://www.readcube.com/articles/10.1155%2F2014%2F732516

baicalein could modulate the expressions and activities of Ca2 + handling proteins, including downregulation of phosphorylation of Ca2 +/calmodulin -dependent protein kinase II (CaMKII) and expression of Na(+)/Ca(2 +)-exchangers (NCX1), upregulation of sarcoplasmic reticulum Ca(2 +) ATPase 2 (SERCA2) and ryanodine receptor 2 (RYR2) http://www.sciencedirect.com/science/article/pii/S0024320515301296

CBD: Can influence the intracellular pH level: Our findings indicate that CBD treatment leads to a biphasic increase in intracellular calcium levels http://jeffreydachmd.com/wp-content/uploads/2014/10/cannabinoids_as_antitumour_agents_Velasco_Sanchez_Manuel_Guzman_2012.pdf

Amiloride: It is proposed that DCB (20 μM) and amiloride (500 μM) impair calcium efflux by NCX, leading to elevations of intracellular calcium that initiate a morphologically necrotic, predominantly caspase-independent glioma cell death. http://jpet.aspetjournals.org/content/310/1/67.abstract

Indeed, stimulation of NHE1 leads to increase of Na than increase of Ca due to a stimulation of the reverse mode of Na/Ca exchange NCX Ref: https://books.google.nl/books?id=5nChwNe1p7gC&pg=PA414&lpg=PA414&dq=nhe+%5BCa2%2B%5Di&source=bl&ots=5duaae_8MD&sig=R2taYd-NJEOIYD2BvjAHik3oy0M&hl=en&sa=X&ved=0ahUKEwiH1bzX8KTJAhXCRg8KHQMKCKoQ6AEIVzAI#v=onepage&q=nhe%20%5BCa2%2B%5Di&f=false

Digoxin: Inhibition of DNA topoisomerases I and II and an increase in the intracellular Ca2+ concentration [41] http://cdn.intechopen.com/pdfs-wm/42589.pdf

Ouabain: Inhibition of DNA topoisomerases I and II and increase in the intracellular Ca2+ concentration [41] http://cdn.intechopen.com/pdfs-wm/42589.pdf


Celecoxib: At the same time, celecoxib has also demonstrated the ability to induce membrane instability independent of these proteins [44]. In the latter case, this most likely occurs as the molecule can penetrate the membrane causing an increase in intracellular calcium ions. The resulting hyperpolarization allows cytochrome c to be dephosphorylated and liberated from the mitochondria. The sequence of events is a hallmark of apoptosis triggered by celecoxib.

Examinations of the biochemical mechanism responsible for this Ca(2+) mobilization indicate that celecoxib blocks endoplasmic reticulum (ER) Ca(2+)-ATPases. Consequently, inhibition of this Ca(2+) reuptake mechanism results in Ca(2+) mobilization from ER stores followed by capacitative calcium entry, leading to [Ca(2+)](i) elevation. In view of the important role of Ca(2+) in apoptosis regulation, this Ca(2+) perturbation may represent part of the signalling mechanism that celecoxib uses to trigger rapid apoptotic death in cancer cells. http://www.ncbi.nlm.nih.gov/pubmed/12076251

Sulindac: Down-regulation of NHE-1, along with an increased [Ca(2+)](i) and induction of intrinsic pathway of apoptosis via activated Calpain 9 could be a putative mechanism pursued by Sulindac and Celecoxib for the chemoprevention of colorectal cancer. http://www.ncbi.nlm.nih.gov/pubmed/22390894

Diclofenac: Intracellular pH and calcium signaling as molecular targets of diclofenac-induced apoptosis against colon cancer. http://www.ncbi.nlm.nih.gov/pubmed/21427588

3-Bromopyruvate: inhibits calcium uptake by sarcoplasmic reticulum vesicles but not SERCA ATP hydrolysis activity http://www.sciencedirect.com/science/article/pii/S1357272512000465  In this study, we show that the sarco/endoplasmic reticulum calcium (Ca(2+)) ATPase (SERCA) type 1 is one of the target enzymes of 3BrPA activity. Sarco/endoplasmic reticulum vesicles (SRV) were incubated in the presence of 1mM 3BrPA, which was unable to inhibit the ATPase activity of SERCA. However, Ca(2+)-uptake activity was significantly inhibited by 80% with 150 μM 3BrPA. These results indicate that 3BrPA has the ability to uncouple the ATP hydrolysis from the calcium transport activities.

Terfenadine-induced apoptosis in human melanoma cells is mediated through Ca2+ homeostasis modulation and tyrosine kinase activity, independently of H1 histamine receptors http://carcin.oxfordjournals.org/content/29/3/500.full TEF induced a very sharp and sustained increase in cytosolic Ca2+ levels in A375 melanoma cells.

PEMF (Pulsed ElectroMagnetic Fields) – We speculate that the window effect observed in this study results from changes in intracellular calcium handling in response to PEMF exposure. Calcium signaling is renowned for its multimodal effects relying on intracellular calcium increments that: 1) result from both calcium influx across the cell surface membrane and release from intracellular membrane-delimited compartments; 2) are simultaneously coded in space, time and holding level; 3) exhibit negative- and positive-feedback regulatory mechanisms and; 4) are coordinated by dynamic changes in membrane organization [32][33]. As a commonly reported consequence of PEMF exposure is elevations of intracellular calcium level [34] one possibility is that PEMFs mediate their effects via influencing intracellular calcium signaling pathways. In the context of this report 3 mT PEMFs at a frequency of 20 Hz for 60 minutes per day would create the “correct” combination of calcium signals that would most effectively result in cell death. Indeed, it has been previously shown that chelating or augmenting intracellular calcium accordingly spares or compromises MCF7 survival, respectively [35][37]http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0072944

Panaxydol from Ginseng – Panaxydol induces apoptosis through an increased intracellular calcium level, activation of JNK and p38 MAPK and NADPH oxidase-dependent generation of reactive oxygen species http://link.springer.com/article/10.1007%2Fs10495-010-0567-8

Resveratrol – Resveratrol induces Ca2 + influx, possibly mediated through T-type Ca2 + channels, with significant selectivity towards mesothelioma cells, suggesting a possible use as an adjuvant to chemotherapy drugs for mesothelioma clinical treatment. http://www.sciencedirect.com/science/article/pii/S0024320516300480

Note: in general the increased intracellular acidity (induced by proton pump inhibitors) leads to increased Calcium accumulation. If we look into the details we will find out that in a way or another the above elements are also intracellular acidifiers. Hyperthermia is also an intracellular acidifier as radiotherapy so these should work together from this point of view.

2. Reducing Intracellular Calcium

T4 hormone: The plasma membrane calcium pump (Ca2+-ATPase) is another ATPase whose transport activity is activated nongenomically by T4: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4383522/  Thyroid hormone regulation of membrane Ca2(+)-ATPase activity http://www.ncbi.nlm.nih.gov/pubmed/2534510/

Ca++-ATPases keep the Ca++ concentration low in the cytosol. One type of Ca++-ATPase is found in the plasma membrane; another is found in the membrane of the endoplasmic reticulum and the sarcoplasmic reticulum of muscle cells. Ref

Remember that T4 depletion has been shown to lead to cancer remission (see the hormons section of this website).

Verapamil: markedly inhibited either corticoidogenesis or Ca2+-influx in response to ACTH  The stimulatory effect of Ca2+ on corticoidogenesis was completely blocked by cycloheximide. https://www.jstage.jst.go.jp/article/endocrj1954/26/2/26_2_227/_article

DCA: causes a decrease in intracellular calcium, potentiating apoptosis in cancer cells and inhibiting proliferation (19, 20). http://www.oicc.ca/uploads/dca-health-professional.pdf

Quercetin: The mechanism of the protective action is also associated with the prevention of increasing the concentration of intracellular calcium and activation of platelets aggregation inhibition processes of thrombogenesis.

Note: this statement is a bit counter intuitive given that Quercetin is a MCT1 inhibitor, i.e. an intracellular acidifier that should than lead to increase intracellular Ca accumulation

Here is a contrasting reference essentially suggesting tha Quercetin leads to intracellular Ca accumulation http://joe.endocrinology-journals.org/content/192/3/527.full

DMSO: reduces the incidence of platelet thrombi (clots in vessels) and reduces the workload of the heart by inhibiting calcium http://www.dmso.org/articles/information/herschler.htm

Berberine: Other possible mechanisms of action on its anti-thrombotic effects are alpha(2)adrenoceptor agonism on platlets[79] and an inhibitory effect on calcium influx. http://examine.com/supplements/Berberine/

Boric Acid: Receptor Activated Ca2+ Release Is Inhibited by Boric Acid in Prostate Cancer Cells – We show B causes a dose dependent decrease of Ca2+ release from ryanodine receptor sensitive stores. This occurred at BA concentrations present in blood of geographically disparate populations. Our results suggest higher BA blood levels lower the risk of prostate cancer by reducing intracellular Ca2+ signals and storage. http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0006009

Cariporide: remarkably suppressed cytosolic Na+ and Ca2+ accumulation. Next, we investigated the effects of cariporide on mitochondria-associated death process. Mitochondrial Ca2+ overload induced by H2O2 was remarkably suppressed by cariporide. http://circ.ahajournals.org/content/108/18/2275

Omeprazole: suspected to lead to intracellular Ca reduction (on long term?) https://clinicaltrials.gov/ct2/show/NCT00582972
PPI long-term use is associated with hypomagnesemic hypoparathyroidism leading to secondary hypocalcemia, which is responsible in the end for the low intracellular Ca as well. However, most patients on long-term PPIs will not develop symptomatic hypomagnesemia [14] unless accompanied by precipitating factors such as gastroenteritis, diuretics. http://www.hindawi.com/journals/crigm/2012/632721/

Genistein: Furthermore, inhibition of tyrosine kinase activity by genistein blocked cytosolic Ca2+ rise and TEF-induced apoptosis. http://carcin.oxfordjournals.org/content/29/3/500.full

Others with anti cancer mechanism connected with intracellular Cancer:

Baicalein: In order to understand the role of Ca2+ in the induction of apoptosis, cells were pre-treated with BAPTA (intracellular calcium chelator) and baicalein. It was shown that the MMP was restored, and the level of cytoplasmic Ca2+ suppressed, the proportion of cells undergoing apoptosis was also markedly diminished. Our data suggest that cellular Ca2+ modulates baicalein-induced cell death via a Ca2+-dependent mitochondrial death pathway in SCC-4 cells. http://www.ncbi.nlm.nih.gov/pubmed/?term=Baicalein+induces+apoptosis+in+SCC-4+human+tongue+cancer+cells+via+a+Ca2%2B-dependent+mitochondrial+pathway

Against the view presented above, there are studies showing that even if blocking Ca accumulation (using e.g. BAPA or Verapamil) some of the elements above or similar (e.g. Ouabain and Valinomycin) are still killing cancer cells and is suggested to be mainly due to the K depletion of those cells: 

To determine the role of this [Ca2+]i increase in ouabain-induced cytotoxicity, the membrane permeable Ca2+ chelator BAPTA-AM was added into the media to prevent the increase in [Ca2+]i. BAPTA-AM (1 μM) effectively prevented ouabain-induced [Ca2+]i increases in LN229 cells (Additional file 2: Figure S2). However, addition of BAPTA-AM did not antagonize ouabain-induced cell death; rather it showed a trend of increasing ouabain-induced cell death in MTT assays. http://bmccancer.biomedcentral.com/articles/10.1186/1471-2407-14-716#MOESM2

Update 2nd Feb 2016: In line with the view presented above, here is a nice publication: Targeting calcium signaling induces epigenetic reactivation of tumor suppressor genes in cancer http://cancerres.aacrjournals.org/content/early/2015/12/30/0008-5472.CAN-14-2391 We performed an epigenetic drug screen using FDA-approved libraries to identify agents that reactivate silenced gene expression in colon cancer cells. In this manner, we identified 3 known epigenetic drugs (DNA methylation and histone deacetylase inhibitors) plus 11 other drugs that were sufficient to reactivate a GFP reporter gene under the control of methylated and silenced CpG island promoters. Notably, these agents also induced the expression of endogenous TSG known to be silenced in multiple cancer cell lines. The newly identified drugs, most prominently cardiac glycosides, did not alter DNA methylation locally or histone modifications globally. Instead, all 11 drugs modulated calcium signaling and triggered calcium-calmodulin kinase (CamK) activity, leading to MeCP2 nuclear exclusion. Blocking CamK activity abolished gene reactivation and cancer cell killing by these drugs, demonstrating that triggering calcium fluxes is an essential component of their epigenetic mechanism of action. Collectively, our findings identify calcium signaling as a new pathway that can be targeted to reactivate TSG in cancer. http://www.sciencedaily.com/releases/2016/02/160209090406.htm


The cytosol is surrounded by two big Ca2+ stores: the extracellular space, where the Ca2+ concentration is ~1.8 mM, and the sarco-endoplasmic reticulum, where the Ca2+ concentration varies from 300 μM to 2 mM.9 In immune cells, the intracellular Ca2+ concentration is ~0.1 μM in the resting state, but it is significantly increased (~10-fold) when the cells are activated.10 http://www.nature.com/cddis/journal/v6/n2/full/cddis201523a.html

Daniel’s note: the above statement is very interesting. In other words, elements such as Salinomycin can lead to activation of the immune system by increasing the intra cellular Calcium in the immune cells!

Cancer as a channelopathy: ion channels and pumps in tumor development and progression. http://www.ncbi.nlm.nih.gov/pubmed/25852478

Calcium Signalling in Cancer Ref

Calcium Channels and Pumps in Cancer: Changes and Consequences https://www.researchgate.net/publication/229438322_Calcium_Channels_and_Pumps_in_Cancer_Changes_and_Consequences

Role of ion channels in regulating Ca2+ homeostasis during the interplay between immune and cancer cells http://www.nature.com/cddis/journal/v6/n2/full/cddis201523a.html

Distinct regulation of pHin and [Ca2+]in in human melanoma cells with different metastatic potential (Ref)

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22 thoughts on “Just another perspective: A Calcium perspective

  1. I don’t know if this article is the best place to say this but i notice a patern in some of the people i met with cancer including my mother.
    They had trouble keeping their teeth before diagnostic, this may not be an issue with all of the people with cancer.
    This brought me to this calcium article in my mind so i had to come back and say it.
    Thank you very much for everything.

    1. Only now I see this comment, but your observation is perfectly inline with my observation. I totally agree this may represent a very relevant aspect and when I find time I will research it carefully. Very good point Alex!

      1. Thank you, i remember i said that because i felt it to be important for disease identification at a more early point, when maybe no suspicion is present.

          1. It is more than that Ovidiu, since it is the case for people with a normal level of D3. There is something more behind and we need to understand what it is.

            1. @Daniel: a possible explanation, the elevation (about 3x) of Osteopontin levels in chronic periodontitis patients, and the role of Osteopontin in proliferation and migration of cancer cells.
              Estimation and comparison of osteopontin levels in plasma in subjects with healthy periodontium and generalized chronic periodontitis and its assessment after scaling and root planing. PMID: 23162328
              Serum Osteopontin Levels Correlate with Clinical and Pathological Features in Non-Small Cell Lung Cancer. PMID: 26856114

          2. i had seen paper on bone tumor case where hypocalcemia along with D3 deficiency was described. This kind of bone tumor produce calcification bone alike objects in soft tissue. Same paper also mentioned that hypocalcemia and vitamin D3 deficiency was gone after tumor was surgically resected.

    1. Thanks a lot J for the credit! I came across this perspective in 2015 when I was researching various substances for the review article on pH we published latter. I felt Ca perspective is a perspective as important as the pH perspective. Interesting to realize how glyco inhibitors can be connected to the Ca story.

      1. D, it is amazing how all these mechanisms are cascading back onto each other. I suspect that even with the calcium idea if you could amplify it and make it highly cancer specific that you could obtain highly impressive results. For example, I was recently reading about a cancer specific form of IP6. Hitting the cancer cells at just the right pressure points could have an overwhelming effect. It is extremely disappointing that so many of these ideas (due to their lack of commercial potential) are never pursued.

    2. Hi J,

      Here is a summary of the article you cited above, just as a reminder for us. They claim the following:

      1. [Ca2+] i is an important regulator of cell apoptosis at all stages, and excessive elevation of intracellular calcium will trigger intrinsic apoptotic pathway, i.e. cancer cell death
      2. Chemotheraphy leads to elevation of intracelular Ca2+
      3. To avoid this and push out Ca2+, cancer cells upregulate a Ca2+ efflux transporter called TRPC5
      4. But the efflux of Ca2+ requires energy (ATP)
      5. To produce this extra energy the cancer cell will upregulate the glucose transporter GLUT1 to absorb more glucose
      6. This glucose is used to produce energy via fermentation or glycolisis
      7 Therfeore, inhibiting either GLUT1 with Phlorizin or Glycolisis via 2DG and/or 3BP will inhibit energy production and lead to Ca2+ accumulation – as a result cancer cell death

      The above, may? also explain why Salinomycin works best after chemotheraphy or 3BP or 2DG since it also leads to a strong Ca+ accumulation.

      1. So… this may be a stupid question, if so… i am sorry. But what about calcium suppliments? Are they a good idea?
        I’m wondering what i can give my mother to make her feel better, stronger and not make a bad choice. In other words, what is good and what is bad for cancer? Wouldn’t hurt to have a page with the basics like with the tips on treatments page. Apologies if that is asking for too much, i’m not as educated. Also, i would do it myself, but i’m asking the stupid question lol 🙂

        Have a great weekend.

      1. There is a problem with Fluoxetine, mice tests showed an increase in brain metastasis, quoting: an effect accompanied by elevated permeability of the blood-brain barrier, pro-inflammatory changes in the brain, and glial activation.
        I tried to post this 3 days ago, but my comment got lost, so now I’m only posting the PMID 25129445.
        IMO Fluoxetine should be only used for short periods, as a chemosensitizer.

  2. The Store operated calcium entry (SOCE) plays a role in proliferation and metastasis. Some approved drugs are SOCE inhibitors, of which Leflunomide, Lansoprazole and Roflumilast are reported to synergize with chemo.
    Nicotine enhances store‑operated calcium entry by upregulating HIF‑1α and SOCC components in non‑small cell lung cancer cells. PMID: 30015910
    Unveiling some FDA-approved drugs as inhibitors of the store-operated Ca2+ entry pathway. PMID: 29038464

  3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5837766/
    Calcium electroporation for treatment of sarcoma in preclinical studies
    (reversible electroporation < 1kV/cm was used on cell and mice)

    Clinical trial
    Histopathologic Effect of Calcium Electroporation on Cancer in the Skin (CAEP-B)
    "In this non randomized phase II study, we will explore histopathological tumour cell death mechanisms in 12 patients with breast cancer metastases and 12 patients with other cutaneous or subcutaneous malignancy."

    p.s. I am looking for information whether CaEP was tried on tumors lesions located beneath the skin without invasive electrodes.
    noninvasive (if feasible) can easily be replicated DIY.

  4. GABAb receptor regulates proliferation in the high-grade chondrosarcoma cell line OUMS-27 via apoptotic pathways
    The GABAB receptor antagonist CGP had anti-tumor effects on high-grade chondrosarcoma cells in a dose dependent manner..
    Furthermore, the changes in intracellular Ca2+ via GABAB receptor-related Ca2+ channels inhibited the proliferation of high-grade chondrosarcoma cells by inducing and modulating apoptotic pathways.
    The GABAB receptor antagonist may improve the prognosis of high-grade chondrosarcoma by exerting anti-tumor effects via different signaling pathways, apoptosis, cell cycle arrest, and Ca2+ channels in high-grade chondrosarcoma cells.

    Note: Interestingly, GABAb receptor is a target for antidepressant drugs, that act as agonist. Whether antidepressants should those be avoided for chondrosarcoma (and in other cancer types as shown below) patients is a question.
    Yet, antagonist for this receptors include among others ginsenosides (according to wiki: https://en.wikipedia.org/wiki/GABAB_receptor)

    GABAb receptors are also found in other tumors as well:

    GABAB Receptor Complex as a Potential Target for Tumor Therapy

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