Drug discovery to override the “immortality” of cancer cells

Every organism is made up of trillions of cells. However, some cells begin to proliferate enormously without being under the control of the regulatory processes in the body, to form a mass of cells leading to a deadly disorder called cancer. Cancer is one of the leading causes of death among the non-communicable diseases in the world. There is no sexual dimorphism seen in the case of cancer, i.e. both men and women are equally susceptible to getting the deadly disorder. The only difference being that the organs that are affected may vary between the sexes.

Cancer can affect any organ with the lungs being the most susceptible. Lung Cancer is the most common type of cancer in both sexes followed by Prostate Cancer in men and Breast Cancer in women. There are several reasons behind the incidence of cancer: lifestyle, exposure to carcinogens, genetics, etc. 

MedPiper Technologies and Journomed conducted a webinar on 6th August 2021, where the various aspects of cancer and Anti-Cancer Drug Discovery for the future were discussed extensively. The speaker Dr. Mohan CD, assistant professor at the Department of Studies in Molecular Biology at the University of Mysore, spoke in detail about the various causes of cancer and what could be some of the possible therapeutic strategies with minimal side effects for treating this scary disorder. 

Dr. Mohan discussed some of the possible risk factors that we come across in our daily lives that can trigger the cancer pathways in our bodies.  

  1. Exposure to Carcinogens: The most common carcinogens are from cigarette smoke which poses a grave threat to both the active and the passive smoker. Many of the green peas that were obtained from the local markets were coated with a potent carcinogen called malachite green in order to make the green peas greener. Melamine is a commonly used material for cookware and it is a common kidney carcinogen. 
  2. Viruses and bacteria: Helicobacter pylori is a bacteria that affects the stomach and causes ulcers. For some people, the infection can progress to gastrointestinal cancer. Many viruses even leave behind parts of their DNA that integrate into the host genome and triggers several cancerous pathways. 
  3. Exposure to radiations: Radiations can alter the host DNA in various ways which can trigger some of the metastatic processes. A CT Scan exposes the person to a high level of radiation and almost 15,000 Americans die due to cancers stemmed from CT Scan exposure. 

Dr. Mohan even discussed some of the key characteristics of cancer cells and what makes them so deadly and hard to treat, some of which include 

  1. Resistant to cell death (apoptosis) 
  2. Has the ability to detach from its point of origin and migrate to other parts of the body (metastasis) and invade other organs. 
  3. Can evade any kind of suppressive signals and has sustained proliferation capacity with a high replication rate 
  4. Do not portray any kind of contact inhibition signals i.e. it does not stop growing even when it comes in contact with any surface or other cells. 

These features confer immortality to the cancer cells. The HeLa cells, which were cervical cancer cells that were isolated from Henrietta Lacks in the early 1950s are still used for cancer research to this date. These cells have still not lost their replicative capacity.

Some of the most common strategies used for treating cancer include surgery, radiation therapy, cytotoxic chemotherapy, molecular targeted therapy and most recently immunotherapy. In chemotherapeutics, drugs from both natural (such as taxol obtained from yew trees) and synthetic origins (methotrexate, sorafenib) are used. Dr. Mohan and his team of researchers work to obtain anti-cancer agents by isolating them from various natural sources and they also synthesize a few of them in laboratory conditions. 

One such chemical the research team synthesized is Azaspirane that was effective against hepatocellular carcinoma preclinical models. They synthesized Azaspirane from using another experimental drug called Atiprimod as a template structure that is being used for treating multiple myeloma. Atiprimod stops the proliferative action of the STAT3 molecules by acting as a JAK2 (Janus kinase) inhibitor. JAK and STAT proteins work together to modulate the various cell cycle proteins. STAT3 is constitutively activated in many types of cancers hence it serves as an excellent anti-cancer target. Azaspirane is different from Atiprimod as it has two six-membered rings in its structure, unlike Atiprimod which has a six-membered ring and a five-membered ring. 

In in vitro conditions, azaspirane reduced the number of viable liver cancer cells at a very low concentration without affecting any of the normal cells. The drug also effectively worked against triple-negative breast cancer (three kinds of receptors are absent) cells by preventing the phosphorylation of STAT3 molecules. Apart from working on these two cell lines, Azaspirane was able to inhibit the growth of a wide range of cancers. In the in vivo studies in mice, there is a decline in the size of the tumor in the liver. Since the chemical is still in its experimental phase, it needs further testing before introducing it into human clinical trials. 

Cancer till date continues to remain a mystery and we still have ways to go in understanding it. Figuring out sustainable therapeutic strategies that have the least side effects is now the main priority in cancer research as it reduces the strain on the healthcare system, increases life-longevity, and gives hope to every cancer patient.

Author: Parvathi Nair

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