Conventional Chemotherapy Along With New Drugs Increase Tumor Cell Death

Highlights

• Cancer is characterized by abnormal cell growth where both cell division and apoptosis (programmed cell death) are impaired partly because of the impairment of the signaling pathway of tumor suppressor agents, such as pRB.
• Cisplatin and 5-FU are conventional drugs that act by inducing DNA damage or preventing DNA production, leading to a reduction of cancer cells.
• Blocking CDKs (a family of proteins responsible for pRB inactivation) activity is the mechanism of action of new anti-cancer drugs when used with conventional drugs in clinical trials.

Inhibitors of proteins that inactivate the tumor suppressor protein pRB, when used along with the conventional anti-cancer drug cisplatin could increase tumor cell death, but have an opposite disastrous effect when used along with 5-FU. In a recent study published in the scientific journal Translational Oncology, researchers from the Federal University of Rio de Janeiro (UFRJ), State University of West Zone, (UEZO) and D’Or Institute for Research and Education (IDOR) tested the therapeutic effect of a combination of conventional - common anti-cancer agents - and new drugs - under clinical trials. "The results were very exciting because the successful outcome depended on the chemotherapy regimens. On the other hand, "wrong" combination of drugs could elicit harmful effects," states Helena Borges, professor at Institute of Biomedical Sciences of UFRJ, and study leader.

Cancer

Cancer starts when cells in a particular part of the body start growing and multiplying abnormally. The disease in a later stage can spread or metastasize to organs and regions outside the origin.

Cancer is one of the leading causes of morbidity and mortality worldwide –

• Cancer affects 8.2 million people per year
• The number of new cases in the US alone will reach 1.6 million in 2017
• Worldwide, the number of new cases is expected to rise by about 70% over the next 2 decades

Cancer’s global impact of a trillion dollars makes it critical to develop new drugs and other novel treatment methods.

Tumor Suppressor Proteins

A tumor suppressor protein acts by suppressing the regulation of the cell cycle or by promoting apoptosis (programmed cell death) or both. This keeps the cells from dividing too fast or in an uncontrolled way and protects them from one step on the path to cancer.

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PRB Protein

Retinoblastoma protein (pRb) was the first tumor-suppressor protein discovered in human retinoblastoma. Cancer’s abnormal pattern of cell growth depends on several signaling mechanisms inside the cells involving pRB.

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pRB plays multiple roles and recently it has also been implicated as a tumor-survival factor.

Functions of pRB include –

• Inhibition of cell cycle progression until a cell is ready to divide
• Stops other proteins from triggering DNA replication (process of DNA making its own copies) before cell division
• Interaction with other proteins to influence cell survival, apoptosis, and the process by which cells mature to carry out special functions (differentiation).

All these control cell division and prevent abnormal growth.

In cancer cells, both cell division and apoptosis do not happen in a timely and organized manner, and are thus impaired because pRB and other tumor suppressor agents are not fully available. PRB protein is dysfunctional in several major cancers.

This finding about the central role of pRB in cancer makes it a potential target for treatments with fewer side effects. Some new drugs that act on the pRB pathway, enhancing its functioning and controlling cell growth to the right amount are under clinical trials and may become alternative anti-cancer treatment soon.

Anti-cancer or Chemotherapeutic Agents

Most of the anti-cancer drugs used today were developed more than 50 years ago, when there was poor knowledge of the cancer-related cellular mechanisms. Two of the chemotherapeutic drugs, cisplatin and 5-FU act by inducing DNA damage or prevent DNA production, thus causing a reduction in the number of cancer cells.

Cisplatin

Cisplatin is a well-known chemotherapeutic drug that was discovered in 1845 and licensed for medical use in 1978/1979. It is effective against various types of cancers and has been used for the treatment of numerous human cancers including bladder, head and neck, lung, ovarian, and testicular cancers. Its mode of action is by interfering with DNA repair mechanisms, causing DNA damage, and subsequently inducing cell death in cancer cells.

However, because of drug resistance, toxicity and numerous undesirable side effects such as severe kidney problems either other platinum-containing anti-cancer drugs have been substituted for cisplatin or it is now used in combination therapies with other drugs.

Fluorouracil or 5-FU

Fluorouracil is used to treat cancer; it was patented in 1956 and came into medical use in 1962. Fluorouracil is given systemically for breast, colorectal, oesophageal, stomach, pancreatic and skin cancers.

5-FU acts principally by inhibiting the action of thymidylate synthase (TS) that is responsible for the synthesis of the pyrimidine thymidine, a nucleoside required for DNA replication. This “thymineless death” causes rapidly dividing cancerous cells to undergo cell death.

The Study

Researchers from Rio de Janeiro studied whether cisplatin and 5-FU

• Would be able to interfere with pRB
• Have an impact on tumor cell death induction and on the standard treatment against cancer

Esophageal cancer is the sixth most common cause of cancer-related death worldwide and pRB’s key role in its signaling pathway is impaired.

PRB expression was first assessed in human esophageal biopsies from non-tumoral tissue, esophageal pre-cancer and advanced stages of disease. This helped in observing a positive correlation between pRB expression and cancer progression; that is ,greater pRB inactivation was found when the esophageal tumor was in a more advanced stage.

"This result reinforces the notion that impaired pRB signaling contributes for the esophageal cancer progression", points Prof. Borges.

The second part of the study focused on a family of proteins called cytokine-dependent kinases or CDKs that are responsible for pRB inactivation. CDK acts by phosphorylation of pRb, thus alleviating the inhibitory effect of pRB and promoting cell cycle progression.

Will blocking CDKs combined with conventional drugs, such as cisplatin and 5-FU, increase cell death, and make the treatment more effective? This is what the researchers wanted to clarify.

Results of The Study

While blocking CDKs’ activity was the mechanism of action of new anti-cancer drugs under clinical trials, the analyses revealed two different effects depending on the chemotherapeutic drug they were paired with. If the cells were treated with

• Cisplatin, the mortality of tumor cells increased
• 5-FU, the resistance of esophageal cancer cells increased, and thus, their death rates decreased

"The results bring attention to studies that investigate the combination of CDKs’ inhibitors and conventional anti-cancer drugs. CDKs’ inhibitors seem to enhance the treatment, but depending on the situation, combining them with 5-FU can be disastrous" says Prof. Borges.

This study highlights the importance of gathering knowledge of cell biology in order to strategically identify and test anti-cancer drugs according to Stevens Rehen, researcher from IDOR and professor at the Institute of Biomedical Sciences/UFRJ, co-author of the study.

New studies have been conducted to investigate the effects of specific CDKs’ inhibitors on new combinations of several types of cancer.
 
Reference:

1. 1. Rossana C. Soletti, Deborah Biasoli, Nathassya A.L.V. Rodrigues, João M.A. Delou, Renata Maciel, Vera L.A. Chagas, Rodrigo A.P. Martins, Stevens K. Rehen, Helena L. Borges. Inhibition of pRB Pathway Differentially Modulates Apoptosis in Esophageal Cancer Cells. Translational Oncology, 2017; 10 (5): 726 DOI: 10.1016/j.tranon.2017.06.008

Source-Medindia