Releasing the Brakes of Cellular Division to Fight Cancer

Introduction

Every day, every hour, every second, cells in the human body constantly divide to form new cells. Some cells divide faster, other slower, but they are all doing that without us even thinking about it. 

A key step in a cellular division process is DNA replication, where the DNA in a mother cell is copied into its two daughter cells.

MCM proteins are essential in the DNA replication machinery (Ref.) and for a long time it was unknown why there is an excess of such proteins inside the cells [“MCM paradox” (Ref.)].

Recent paper published in the prestigious journal Nature, shows that this excess is used by cells to slow down the DNA replication (Ref.1, Ref.2). Scientists suggest that MCM proteins work as “speed bumps” to slow down the traffic and help cells deal with imperfections (Ref.). On the other hand, if DNA is replicated too quickly, it can be fatal for the cell. It is like driving a car on a road that sometimes has potholes. If we drive the car slow enough, we can avoid them while driving too fast we risk going right into the pothole and brake the car.

Next to MCM proteins that help to slow down the DNA replication process, there is another protein called MCMBP. MCMBP takes care of MCM proteins and escorts them to DNA, like a “babysitter”, where MCM can be useful and do their job as “speed bumps” in the replication process.

Without MCMBP, new formed cells inherit only half of the required MCM which causes DNA damage as a result of overly fast replication (Ref.).

While the DNA of a normal cell can be seen as a nice and clean road, the DNA in cancer cells is seen as a road full of “potholes”. On this line scientists came up with an idea to try to kill cancer by manipulating MCMBP to affect MCM. The idea is to inhibit MCMBP, and with that lower the amount of MCM in new formed cells. This in turn allows an increase in speed of DNA replication, which can be tolerated by normal cells but it is expected to be lethal to cancer cells (Ref.).

Indeed, it has been recently showed that high speed of cellular division induces DNA replication stress and genomic instability (Ref.). In addition, it has been shown that high expression of MCM proteins may predict worse prognosis of cancers (Ref.1, Ref.2). This indicates that, fast deviding cells need more “speed bumps” in order to mantain a successful cellular division and progess.

Therefore, lowering MCMNP and/or MCM is a relevant idea to be applied as a part of a more comprehensive approach. However, the question is what are the available MCMBP inhibitors.

MCMBP and MCM inhibitors

Food Supplements:

Withaferin A from Withania somnifera, known commonly as Ashwagandha (found online as a food supplement), has been suggested to bind and inhibit MCMBP, explaining observed anti cancer effects related to Withaferin A (such as halted G2/M entry) (Ref.).

Genistein,  a natural, nontoxic dietary isoflavone found as a food supplement inhibits MCM (MCM2) in prostate cancer (Ref).

Drugs: 

Ciprofloxacin is an available FDA approved antibiotic that was shown to be an MCM inhibitor (MCM 2-7) (Ref.)

Simvastatin, an FDA approved drug inhibits MCM (MCM-7) (Ref.) and inhibits the growth of tamoxifen-resistant breast cancer cells (Ref.)

Atorvastatin, an FDA approved drug inhibits MCM (MCM 6-7) (Ref.)

Lovastatin, an FDA approved drug inhibits MCM (MCM 2) with anti-proliferation action in non-small cell lung carcinomas (Ref.) 

Metformin, an FDA approved drug inhibits MCM (MCM 2) increases chemo-sensitivity of colorectal cancer cells (Ref.)

Previously, we have seen that Metformin, Statins and Antibiotics act against cancer cells by modulating metabolic pathways. It’s interesting to now see yet another angle through which these drugs act against cancer. Whether it is their metabolic action that leads to inhibition of MCMs or is a direct non-related action it is still an open question to me. Nevertheless, this only makes stronger the position of these re-purposed drugs in oncology.

MCMBP and MCM inhibitors to increase chemo and radio-therapy effectiveness

It has been recently showed in another Nature paper that PARP inhibitors induce replication stress, simultaneously making cells unreceptive to cellular division defects, a property beneficial in highly proliferative cancers (or stages). It has also been suggested that combination of PARP inhibitors with cellular division damaging chemotherapy (Ref.) and radiotherapy (Ref.) can be a good idea to enhance the damage induced to cancer cells.

Therefore, combining MCMBP and MCM inhibitors with PARP inhibitors and/or chemotherapy/radiotherapy may amplify the damage produced to cancer cells even more. In other words, it makes very much sense to ad repurpused drugs such as Metformin or Statins during chemo or radiotherapy (note: as mention elsewhere, when Metformin is used, I woudl always remove it 3 days before chemo if possible and add it back starting with the chemo day).

PARP inhibitors have been recently approved for treating e.g. ovarian (Olaparib, Rucaparib, Niraparib) breast (Talazoparib) and prostate cancer (Rubraca, Lynparza).

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References

High speed of fork progression induces DNA replication stress and genomic instability https://www.nature.com/articles/s41586-018-0261-5

Accurate replication of DNA requires stringent regulation to ensure genome integrity. In human cells, thousands of origins of replication are coordinately activated during S phase, and the velocity of replication forks is adjusted to fully replicate DNA in pace with the cell cycle1. Replication stress induces fork stalling and fuels genome instability2. The mechanistic basis of replication stress remains poorly understood despite its emerging role in promoting cancer2. Here we show that inhibition of poly(ADP-ribose) polymerase (PARP) increases the speed of fork elongation and does not cause fork stalling, which is in contrast to the accepted model in which inhibitors of PARP induce fork stalling and collapse3. Aberrant acceleration of fork progression by 40% above the normal velocity leads to DNA damage. Depletion of the treslin or MTBP proteins, which are involved in origin firing, also increases fork speed above the tolerated threshold, and induces the DNA damage response pathway. Mechanistically, we show that poly(ADP-ribosyl)ation (PARylation) and the PCNA interactor p21Cip1 (p21) are crucial modulators of fork progression. PARylation and p21 act as suppressors of fork speed in a coordinated regulatory network that is orchestrated by the PARP1 and p53 proteins. Moreover, at the fork level, PARylation acts as a sensor of replication stress. During PARP inhibition, DNA lesions that induce fork arrest and are normally resolved or repaired remain unrecognized by the replication machinery. Conceptually, our results show that accelerated replication fork progression represents a general mechanism that triggers replication stress and the DNA damage response. Our findings contribute to a better understanding of the mechanism of fork speed control, with implications for genomic (in)stability and rational cancer treatment.

Broad-spectrum antitumor properties of Withaferin A: a proteomic perspective https://pubs.rsc.org/en/content/articlelanding/2020/md/c9md00296k#!divAbstract

The multifunctional antitumor properties of Withaferin A (WA), the manifold studied bioactive compound of the plant Withania somnifera, have been well established in many different in vitro and in vivo cancer models. This undoubtedly has led to a much better insight in the underlying mechanisms of WAs broad antitumor activity range, but also raises additional challenging questions on how all these antitumor properties could be explained on a molecular level. Therefore, a lot of effort was made to characterize the cellular WA target proteins, since these binding events will lead and initiate the observed downstream effects. Based on a proteomic perspective, this review provides novel insights in the molecular chain of events by which WA potentially exercises its antitumor activities. We illustrate that WA triggers multiple cellular stress pathways such as the NRF2-mediated oxidative stress response, the heat shock response and protein translation events and at the same time inhibits these cellular protection mechanisms, driving stressed cancer cells towards a fatal state of collapse. If cancer cells manage to restore homeostasis and survive, a stress-independent WA antitumor response comes into play. These include the known inhibition of cytoskeleton proteins, NFκB pathway inhibition and cell cycle inhibition, among others. This review therefore provides a comprehensive overview which integrates the numerous WA–protein binding partners to formulate a general WA antitumor mechanism.

Researchers solve ‘protein paradox’ and suggest way to exploit cancer weakness https://www.sciencedaily.com/releases/2020/10/201022112601.htm

Researchers solve long-standing ‘protein paradox’ and suggest way to exploit cancer weakness (Ref.)

Equilibrium between nascent and parental MCM proteins protects replicating genomes https://www.nature.com/articles/s41586-020-2842-3

Minichromosome maintenance proteins (MCMs) are DNA-dependent ATPases that bind to replication origins and license them to support a single round of DNA replication. A large excess of MCM2–7 assembles on chromatin in G1 phase as pre-replication complexes (pre-RCs), of which only a fraction become the productive CDC45–MCM–GINS (CMG) helicases that are required for genome duplication1,2,3,4. It remains unclear why cells generate this surplus of MCMs, how they manage to sustain it across multiple generations, and why even a mild reduction in the MCM pool compromises the integrity of replicating genomes5,6. Here we show that, for daughter cells to sustain error-free DNA replication, their mother cells build up a nuclear pool of MCMs both by recycling chromatin-bound (parental) MCMs and by synthesizing new (nascent) MCMs. Although all MCMs can form pre-RCs, it is the parental pool that is inherently stable and preferentially matures into CMGs. By contrast, nascent MCM3–7 (but not MCM2) undergo rapid proteolysis in the cytoplasm, and their stabilization and nuclear translocation require interaction with minichromosome-maintenance complex-binding protein (MCMBP), a distant MCM paralogue7,8. By chaperoning nascent MCMs, MCMBP safeguards replicating genomes by increasing chromatin coverage with pre-RCs that do not participate on replication origins but adjust the pace of replisome movement to minimize errors during DNA replication. Consequently, although the paucity of pre-RCs in MCMBP-deficient cells does not alter DNA synthesis overall, it increases the speed and asymmetry of individual replisomes, which leads to DNA damage. The surplus of MCMs therefore increases the robustness of genome duplication by restraining the speed at which eukaryotic cells replicate their DNA. Alterations in physiological fork speed might thus explain why even a minor reduction in MCM levels destabilizes the genome and predisposes to increased incidence of tumour formation.

MCMs in Cancer: Prognostic Potential and Mechanisms https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7023756/

Breviscapine (BVP) inhibits prostate cancer progression through damaging DNA by minichromosome maintenance protein-7 (MCM-7) modulation https://www.sciencedirect.com/science/article/abs/pii/S0753332217314890

Quantitative Proteomics Reveals Dynamic Interactions of the Minichromosome Maintenance Complex (MCM) in the Cellular Response to Etoposide Induced DNA Damage https://www.mcponline.org/content/14/7/2002

The Human Replicative Helicase, the CMG Complex, as a Target for Anti-cancer Therapy https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5885281/

DNA helicases unwind or rearrange duplex DNA during replication, recombination and repair. Helicases of many pathogenic organisms such as viruses, bacteria, and protozoa have been studied as potential therapeutic targets to treat infectious diseases, and human DNA helicases as potential targets for anti-cancer therapy. DNA replication machineries perform essential tasks duplicating genome in every cell cycle, and one of the important functions of these machineries are played by DNA helicases. Replicative helicases are usually multi-subunit protein complexes, and the minimal complex active as eukaryotic replicative helicase is composed of 11 subunits, requiring a functional assembly of two subcomplexes and one protein. The hetero-hexameric MCM2-7 helicase is activated by forming a complex with Cdc45 and the hetero-tetrameric GINS complex; the Cdc45-Mcm2-7-GINS (CMG) complex. The CMG complex can be a potential target for a treatment of cancer and the feasibility of this replicative helicase as a therapeutic target has been tested recently. Several different strategies have been implemented and are under active investigations to interfere with helicase activity of the CMG complex. This review focuses on the molecular function of the CMG helicase during DNA replication and its relevance to cancers based on data published in the literature. In addition, current efforts made to identify small molecules inhibiting the CMG helicase to develop anti-cancer therapeutic strategies were summarized, with new perspectives to advance the discovery of the CMG-targeting drugs.

Disclaimer

This site is not designed to and does not provide medical advice, professional diagnosis, opinion, treatment or services to you or to any other individual. Through this site and linkages to other sites, I provide general information for educational purposes only. The information provided in this site, or through linkages to other sites, is not a substitute for medical or professional care, and you should not use the information in place of a visit, call consultation or the advice of your physician or other healthcare provider. I am not liable or responsible for any advice, course of treatment, diagnosis or any other information, services or product you obtain through this site. This is just my own personal opinion regarding what we have learned on this road.

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6 thoughts on “Releasing the Brakes of Cellular Division to Fight Cancer

  1. Thank you Daniel.

    I’m guessing more and more information about the benefits of Metformin and Statins are revealed. So looking at these pills i wonder, would it not be a good ideea to stay away (not fully because it’s impossible) from cholesterol and sugar, for disease prevention only.

    Thank you again for all the hard work and friendship.
    Best wishes.
    Alex

  2. Dear Daniel & Alex,

    I have been prowling your website for a while but just mustered the courage to write in. So happy to see Alex still around! A lot happened to me since I last commented here. My dear Mom died in the spring of 2018 (of ovarian cancer) and it was very hard to bear. Both her death and the road leading there. I was the almost her sole caretaker, staying with her in her last 4 months and myself feeling quite ill, weak and down. More about that later. How have you been, both? I was trying to look up Alex here but didn’t find anything recent, that is why I was so happy to have found him now. How is Ergin, is he still around? My impression is that there is a lot less traffic on this website than there used to be. The reason could be that your website is not so easy to find any more. Unless I type in the address, it is not to be found with a google search, I think. I might be wrong, of course.

    Hope to hear from you both,
    Helga

    1. Dear Helga,

      Very nice to hear from you, and I am so sorry to hear about the passing of your dear mom. Ergin is not around anymore, but we speak from time to time by e-mail. He is following his dream and getting great results in agriculture – he sold the company of his dad in electronics and is mainly focused on the agriculture. He stopped writing here due to own health challenges. The traffic on the website is actually about double compared to the time when you, Ergin and Alex were writing here (but lower compared to the beginning of this year due to the reason mentioned below). However, the discussions at this point are less intense, and this intensity comes in cycles. Myself, I also have much less time to be actively involved in writing comments as I need to focus on the success of the supplement company we started this year (MCS Formulas) – the success here is the only chance for me to stay in the oncology field. You are right that Google started to create a gap between the information such as shared on this website and people in search for this. They have implemented special algorithms. The largest impact I could see, was sometimes in March this year, when they dropped the number of visits brought by Google searches to here. Fortunately, people share the information posted on cancetreatmentsresearch.com via social media platforms and this allows the exposure of information. Also, the relatively large number of registered people represents a good major channel through which the information can flow directly, beyond the gaps created by search engines. Again, very nice to hear from you!

      Have a very nice weekend!

      Kind regards,
      Daniel

  3. Dear Daniel,

    Thanks so much for your kind response. Sorry to hear about Ergin’s health concerns. I hope it is nothing serious. I hope Alex is ok, it was such a great conversation with them (and of course with you). I sometimes link and mention this website on social media but I’d never find this site now if I didn’t know about it already.

    I bet it is very hard to sell stuff considering the circumstances. I wonder how you are doing in this respect? Do you have your own production company, etc.
    I wonder also when you site sends notifications about responses. I didn’t receive an email about your response (to my comment here). I found it because the page was still open in my browser.

    Anyway, I hope you are doing well. I’ll send you an email.

    All my best,
    Helga

    1. HI Helga,

      Thank you for your msg here and for the e-mail. Email responded, now your comment 🙂

      Ergin had to deal with something serious to my knowledge but his last e-mail was very nice, kind and balanced, and he was happy with the results of his work in agriculture space. With Alex I always want to find time to speak on Skype but days, weeks, months are just flying away …

      I do what I can with teh visibility of this website, but there is so much that one person alone can do …. there is so much more that I would like to do …. also keeping updates on cases with whom I am in contact, successful and not successful … but too much for me alone – I hope one day I will not be alone anymore with all this.

      About the company we can speak more on the call that we could have as proposed in the e-mail. There is a lot to say, and a lot of good things happening. I can see how God aligns things to happen on that line. But of course the workload is considerable as we are having a wide range of supplements and working with multiple partners. We had challenges shipping around the World as some shipping companies are doing a good job in one area of the world and less good in another. But now we have a great partnership with FedEx and shipp most of the orders with that in a very fast and reliable manner. This is one essential aspect for any supplement company, and I am happy we can have this to deliver in just 1-2 days to countries such as UK, Spain, France, 2-4 days to e.g. US and about 4-6 days to Australia. To me thsi is crazy fast 🙂 Anyway, we can discuss these points on the phone.

      Have a good night!

      Kind regards,
      Daniel

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