New Breast Cancer Treatment Shows Promise Against Drug-Resistant Tumors

The research team, led by investigators studying azetidine-2-one compounds—molecules containing a four-membered ring structure—created a series of new drugs by modifying combretastatin CA-4, a naturally occurring anti-cancer agent derived from the South African tree Combretum caffrum.

Targeting Multiple Cancer Types

The modified compounds demonstrated remarkable potency against MCF-7 breast cancer cells, with several showing effectiveness at nanomolar concentrations. Compound 12l emerged as particularly promising, inhibiting cancer cell growth at just 10 nanomolar in breast cancer cells and an even more impressive 3 nanomolar in HT-29 colorectal cancer cells.

Notably, while the original combretastatin CA-4 showed poor activity against the drug-resistant HT-29 colon cancer cells, compound 12l proved over 1,000 times more potent. This dramatic improvement stems from modifications that prevent the compound from being inactivated by the body's natural detoxification processes.

Smart Drug Design

The researchers achieved this breakthrough by strategically removing one methoxy group from the drug's structure. Using advanced computer modeling and molecular dynamics simulations, they demonstrated that this modification doesn't compromise the compound's ability to bind to its target—tubulin, a protein essential for cell division—while improving its effectiveness against resistant cancer cells.

Importantly, the compounds showed minimal toxicity in preliminary tests, with low levels of cellular damage at therapeutic concentrations. The lead compound also exhibits favorable drug-like properties, making it a suitable candidate for further development.

The findings represent a significant step forward in addressing the challenge of drug resistance in cancer treatment, particularly for colorectal cancer where resistance remains a major clinical obstacle.