Lethal agents: Some tumours are robust enough to resist chemotherapy

In a small flask, a dense cluster of cancer cells shows off not just immortality ? the hallmark of tumours ? but a bit of deviousness as well. When a scientist at the Rajiv Gandhi Centre for Biotechnology (RGCB) in Thiruvananthapuram pours a lethal anti-cancer drug into the beaker, the cells are expected to die. But they don?t. They are drug-resistant tumours, armed with the ability to survive the action of cancer drugs.

Biologist Devarajan Karunagaran at the RGCB has spent the past seven years trying to unravel the tricks that tumour cells employ to evade chemotherapeutic drugs. Now, drawing on his studies, researchers at the RGCB have shown that curcumin, the ingredient in turmeric that gives the spice its yellow colour, may be able to turn drug-resistant tumours susceptible to taxol, a drug widely used in the chemotherapy of some cancers.

The new study by Dr Ruby John Anto and her colleagues in the cancer biology division at the RGCB provides fresh evidence that taxol and curcumin may be more effective against drug-resistant tumours than taxol alone. While scientists abroad have shown that curcumin has the ability to enhance the killing power of some anti-cancer drugs, this is the first study that describes the biological mechanisms through which the ingredient of the age-old Indian spice achieves this result.

John Anto and her colleagues examined the effect of a combination of curcumin and taxol on cells of cervical cancer, the second most common cancer among women worldwide. In a report that has been accepted for publication in the Journal of Biological Chemistry, the RGCB scientists said that curcumin can make tumour cells sensitive, or more susceptible, to the chemotherapeutic action of taxol, the best anti-cancer compound isolated so far from plants.

Curcumin and taxol, when used in combination, induces almost double the amount of cell death compared to taxol alone, the scientists said in their paper. ?The importance of this study is that it demonstrates the mechanism by which curcumin can make taxol more effective at tumour-killing,? says Karunagaran, a senior scientist at the RGCB who began to study the genetics of drug resistance in tumours in the late 1990s.

Anti-cancer drugs, such as taxol, kill tumour cells by inducing apoptosis, or cellular suicide, by the tumour cells. ?But cancer cells can be very devious,? says Karunagaran. His earlier studies had shown that cancer cells ?learn? to survive the onslaught of drugs through two mechanisms, both of which are designed to evade apoptosis. The tumour cells acquire mutations in genes that play a role in apoptosis, and they begin to ?overexpress anti-apoptotic genes.?

?Both the mutations in pro-apoptotic factors and the overexpression of anti-apoptotic genes help the tumours evade death,? says Karunagaran.

In their experiments, Anto and her colleagues have shown how curcumin interferes with such tricks employed by drug-resistant tumour cells. She focused on two anti-apoptotic mechanisms that involve an enzyme called Akt kinase and a protein called nuclear factor KB. ?Both the enzyme and the protein are anti-apoptotic factors ? the higher the levels of these substances in a tumour cell, the more resistant it is to the effect of anti-cancer drugs,? says John Anto.

Low doses of taxol can activate anti-apoptotic factors, making tumours resistant. ?This necessitates the use of high doses for effective chemotherapy, but the high doses can cause toxicity in patients,? says John Anto. ?Our studies show that curcumin may allow the use of lower doses of taxol for effective chemotherapy.?

The studies have shown that curcumin reduces the levels of both the enzyme and the protein in tumour cells, thus making them more vulnerable to the action of taxol. In their experiments, John Anto and her students exposed drug-resistant cancer cells to a low dose of curcumin, waited for two hours and then exposed the cells to taxol.

They found that using curcumin before taxol enhanced the killing power of taxol thro-ugh apoptosis. The increased death of tumou-rs was due to the taxol-induced apoptosis alone and not through the effect of curcumin which is also known to kill tumours at high doses.

Interestingly, the study also showed that curcumin did not enhance the taxol-induced apoptosis in normal cervical cells. The synergistic effect of curcumin was observed only in cancer cells whose resistance to apoptosis had been induced by taxol itself. John Anto says she is now trying to repeat similar experime-nts in cells from cancers of the colon, breast and ovaries. The next step will involve establishing this action of curcumin in animals.

Karunagaran continues to investigate how tumour cells acquire resistance to drugs and how curcumin may hold the key to solving this problem. In a related study accepted last week for publication in the journal Carcinogenesis, the researchers have shown that colon cancer cells lacking a pro-apoptotic gene called Bax are resistant to the anti-cancer effect of curcumin. ?The long-term goal is to find ways to overcome drug-resistant tumours,? says Karunagaran.