Pharma Focus Asia

The Potential of Cell Free Chromatin Inhibition in Cancer

A comment

Divya S Mishra, Board Certified Oncologist

Even as precision therapeutics sets its sight into jet-age, the ‘back to basics science’ jolts it back to a reality check of possibilities on the ground!  Researchers from Tata Medical Centre are India using a nutraceutical combination in early clinical trials to improve cancer outcomes and have recently provided an update on the clinical research efforts in this regard1. The discussion below reminds us how our attention to Redox homeostasis in the human body is elemental to disease prevention, better treatment efficacy and toxicity management and holds immense promise for cancer patients worldwide.

Since 2017, seminal work by Dr. Mitra from Tata Medical Centre has been done on Cell-free chromatin particles (cfChPs) that are released upon cell death2. When cancer cells die, the skeletons of mutated cell free chromatin may not always get buried in the tumor microenvironment, but may escape the overwhelmed endogenous scavenging mechanisms and immune surveillance to roam about freely through the peripheral blood. During this time, they can wreak havoc by gaining entry in to the houses of normal healthy cells by integrating into their DNA and damaging it. They also inflict mitochondrial damage, enhance free radical (reactive Oxygen species, ROS) production and perpetuate inflammation. It has been shown through preclinical and exploratory studies that cfChPs have the potential to cause enhanced chemotherapy related toxicity and immune activation of cancer cells thereby enhancing their survival.

Oxidative stress due to free radicle generation leads to altered inflammation that then acts as a precancerous state of host cells leading to the initiation of genetic mutations and impaired gene regulation. Antioxidants alone can remove free radicals and prevent tumorigenesis but this must be balanced by prooxidant action to ensure damaged cells don’t benefit from the cell preserving (anti apoptotic) action of free radical clearance. This is how endogenous antioxidant mechanisms handle the dynamics of onslaught that our bodies are subjected to, on a daily basis, but may become overwhelmed from time to time3. In Cancer cells an innately high level of intracellular reactive oxygen species (ROS) exists and the same antioxidant may act as potent pro-oxidant molecules and trigger ROS-mediated apoptosis. However, at least three factors can influence the function of an antioxidant transforming it to a prooxidant; these factors include the presence of metal ions, the concentration of the antioxidant in matrix environments and its redox potential and forms the basis of exogenous interventions. The picture below describes the key differences between a normal and a cancer cell and the impact of antioxidant- prooxidant function of carotenoids4.

 Chromatin Inhibition in Cancer

Dr. Mitra and colleagues have attempted inhibition of cfChPs with a Prooxidant combination of Resveratrol (an antioxidant) and Copper in carefully selected doses, thus promising wide ranging therapeutic possibilities. The favorable biological consequences have recently made news through recent reports of exploratory and early phase clinical trials with the combination in oral cancer, gastric cancer and multiple myeloma. Resveratrol is a well-known polyphenolic plant derived antioxidant compound and there are numerous studies associating it’s beneficial effects in cancer and in cardio- and neuro-protective effects5. In the combination, it reduces Cu(II) to Cu(I) generating reactive Oxygen species (ROS) and achieving DNA degrading activity at optimum concentrations desirable for anticancer activity6.

Such reverse engineering to curb the downstream effects of cancer cell death due to disease and drugs through down regulation of cancer hallmarks and immune checkpoints of cancer cells may yield far reaching benefits in ensuring a non-toxic, broadly applicable and affordable options for cancer patients.

If cancer cells appreciated a peaceful burial of their skeletons, in return for sparing misery to patients afflicted with cancer, then the handling of cfChP’s by this prooxidant combination would win their hearts. The results of investigations and later stage clinical trials are eagerly anticipated.

References:

  1. https://tmc.gov.in/tmh/pdf/TMC_Statement_Res_Cu_01_03_24.pdf
  2. Chaudhary S, Mittra I. Cell-free chromatin: A newly described mediator of systemic inflammation. J Biosci. 2019 Jun;44(2):32. PMID: 31180045.
  3. Mahanta, S.K., Challa, S.R. (2022). Phytochemicals as Pro-oxidants in Cancer. In: Chakraborti, S. (eds) Handbook of Oxidative Stress in Cancer: Therapeutic Aspects. Springer, Singapore. https://doi.org/10.1007/978-981-16-1247-3_209-1
  4. Shin, J.; Song, M.-H.; Oh, J.-W.; Keum, Y.-S.; Saini, R.K. Pro-oxidant Actions of Carotenoids in Triggering Apoptosis of Cancer Cells: A Review of Emerging Evidence. Antioxidants 2020, 9, 532. https://doi.org/10.3390/antiox9060532
  5. Andrés CMC, Pérez de la Lastra JM, Juan CA, Plou FJ, Pérez-Lebeña E. Polyphenols as Antioxidant/Pro-Oxidant Compounds and Donors of Reducing Species: Relationship with Human Antioxidant Metabolism. Processes. 2023; 11(9):2771. https://doi.org/10.3390/pr11092771
  6. https://www.prnewswire.com/news-releases/indian-researchers-from-actrec-discover-novel-therapeutic-agent-for-a-host-of-diseases-301722380.html

Disclaimer: This article represents my personal views and is not representative of that of my company or any organisation I am associated with.

Divya S Mishra

Divya Mishra is a board certified oncologist with over 17 years’ experience in the pharmaceutical/CRO industry, clinical practice, and academia, in areas of oncology/haematology, family medicine, palliative medicine, and outcomes research. Mishra has worked across multiple geographies and diverse, multicultural settings for organisations such as Pfizer, IQVIA, and SFJ. She is currently working at ICON as a medical director and therapeutic expert for the oncology/haematology disease areas in the APAC region, based in the regional headquarters in Singapore.

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