Acidic pH reduces the effectiveness of cancer drugs

Acidic pH reduces the effectiveness of cancer drugs

Cancer remains one of the major public health challenges facing society today. Despite advances in cancer treatments, the WHO estimates that the disease will cause a staggering 9.6 million deaths in 2018 making it the second leading cause of death worldwide. Sadly, cancer rates will likely increase in the near future due to the aging global population and high rates of unhealthy lifestyle choices such as smoking and obesity. Managing these increasing cancer rates into the future, will require the development of better and more effective cancer treatments.

However, discovering new cancer drugs is a very costly and time-consuming process. Scientists usually start with a library of chemicals consisting of thousands of different drug molecules. These drug molecules are then individually tested against cancer cells that are grown in the laboratory to see if they contain any potent anticancer activity. Promising candidate molecules that kill these cancer cells then undergo testing in laboratory animals before being eventually tested in humans. Unfortunately, the current drug discovery process is relatively inefficient meaning that a large number of molecules that kill cancer cells in the laboratory are not effective in treating actual cancer tumours in humans.

One possible reason for this is that the cancer cells that are used in the initial screening process do not accurately reflect the behaviour of actual cells present in human tumours. During drug screening, cells in the laboratory are fed with abundant nutrients, high oxygen levels and maintained at close to neutral pH values. These are conditions that are suited for growing healthy tissues.

In contrast, tumour cells often lack access to nutrients and oxygen, due to  abnormal blood vessel formation around the tumour. Apart from carrying nutrients, blood vessels also normally help remove waste generated by cells. If waste products cannot be carried away,  they build up and turn s the pH of the tumour environment acidic. Interestingly, cancers cells seem to have adapted to use this acidic environment to its advantage. Studies have suggested that acidic pH might help increase the ability of cancer cells to spread. There is also evidence to suggest that acid pH helps cancer cells resist the effects of some anti-cancer drugs by altering the chemical charge  of the drug molecules and making it harder for them to enter the cancer cells. This acidic environment could be a reason why many promising drug molecules identified in initial laboratory screens fail to kill actual cancer cells in humans.

Clearly, better methods of mimicking the actual tumour environment would be the key to identifying more effective anti-cancer drugs.  To address this need, a team of Swedish scientists have developed a new cancer cell line that had been adapted to grow under acidic conditions. They developed this cell line by continuously growing a batch of human colon cancer cells in a specialised broth containing acid pH for 3 months. By constantly exposing the cell line to acid pH over several generations, the researchers were able to create an entirely new cell line that has evolved to thrive in this acidic environment.The team observed that these acid-adapted cells had numerous differences in shape and metabolic activity compared to their unadapted parents strongly suggesting that adapting to this acidic environment causes significant changes to the cells themselves.

Apart from physical and metabolic changes, the team then tested whether these acid-adapted cells were indeed more resistant to anti-cancer drugs. To do this, they examined the survival rate of these cells when exposed to a panel of well-known anti-cancer drugs. They found that most of these drugs were less effective at eliminating the acid-adapted cells compared to unadapted cells confirming their suspicions that acid pH might play a key role in cancer resistance to treatment.  

The team then wanted to determine whether their acid-adapted cells could be used to identify anti-cancer molecules that were effective even under acidic conditions. The researchers tested a library of 1280 different FDA-approved drugs for activity against the acid-adapted cells and found that 11 of these drugs showed potent anti-cancer activity. One drug in particular, Verteporfin, was particularly effective against the cells. Interestingly, the drug is currently only approved to treat an eye disease called macular degeneration but is also being tested as a potential treatment for pancreatic cancer.

The exact reason why Verteporfin is effective at killing acid-adapted needs further investigation. The team thinks that this could be because of the unique chemical makeup of Verteporfin that allows it to easily pass through cell membranes, accumulate inside the cells, and subsequently kill them even under acidic pH.

Because of its anti-cancer abilities in the laboratory, the team believes that Verteporfin might be a promising candidate for further clinical trials to confirm its efficacy in eliminating different types of tumours in humans. The team also hopes that the acid-adapted cells that they have developed would be adopted by other researchers as a screening tool to make cancer drug discovery more efficient in the future.

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