There are two problems with the current chemotherapy and radiotherapy.  Neither can kill all cancer cells at the end of the treatment, and the surviving cells become resistant to the treatments which make further treatments ineffective for the same disease.  As a result, a patient cannot achieve a long term survival.

A new study published in Cell Death and Disease shows that gemcitabine - an important chemotherapy marketed by Eli Lilly and Company, can kill pancreatic cancer cells, but also induce drug resistance which can eventually lead to loss of the efficacy of the drug against the cancer.  

The study led by I Herr at University of Heidelberg in Heidelberg, Germany and colleagues also demonstrates that naturally occurring anticancer agents such as isothiocyanate sulforaphane in cruciferous vegetables and quercetin in many fruits and vegetables kill pancreatic cancer cells just like gemcitabine, but without inducing drug resistance.

These findings suggest that even though no therapy can kill all pancreatic cancer cells at the end of a treatment period, patients treated with natural therapies like isothiocyanate sulforaphane or quercetin can continue using the same therapy to suppress the progression of the cancer and achieve a long term survival but those who are treated with gemcitabine will soon find the drug useless and they cannot live as long as those treated with natural therapy.

The study

For the study, the researchers treated gemcitabine-sensitive pancreatic cancer cells (BxPC-3 cells), non-malignant ductal pancreas cells, and mesenchymal stromal cells with gemcitabine or isothiocyanate sulforaphane or quercetin to see how these treatments affect the different cells in terms of their efficacy and drug resistance.  

The study shows that treatment with either isothiocyanate sulforaphane or quercetin induced apoptosis and reduced viability in the pancreatic cancer cells, but not in the normal cells.  This indicates that these natural anticancer agents have a selective cancer killing effect against pancreatic cancer cells.

Drug resistance often develops after a long-term treatment, particularly in high doses.  So the researchers treated BxPC-3 cells with gemcitabine, sulforaphane or quercetin in increasing doses for more than one year and then selected the surviving subclones Bx-GEM (cancer cells treated with gemcitabine), Bx-SF (cancer cell treated with isothiocyanate sulforaphane) and Bx-Q (cancer cells treated with quercetin) to test their drug resistance.

The test results show that Bx-GEM cells developed total resistance to the chemotherapy after the treatment, while Bx-SF and Bx-Q cells remain largely sensitive to sulforaphane and quercetin, respectively, after their treatment.

Further laboratory studies of these subclones find cancer stem cell features and tumor progression biomarkers enriched in gemcitabine-resistant cells, but decreased in sulforaphane- and quercetin-treated cancer cells.  This means that the chemotherapy made the cancer cells more aggressive while sulforaphane and quercetin made the cells less aggressive.

In animal studies of the subclones, mice receiving the sulforaphane- (Bx-SF) or quercetin-treated (Bx-Q) pancreatic cancer cells developed "almost undetectable tumors" or small tumors while those receiving gemcitabine-resistant cells (Bx-GEM cells) formed large tumors.

"This study demonstrates that the continuous exposure of pancreatic cancer cells to sulforaphane or quercetin does not induce resistance in surviving cells but reduces tumorigenicity by inhibition of tumor progression markers. These results highlight that cancer cells may not adapt to the preventive and therapeutic effects of a regular fruit- and vegetable-based diet," the study concludes. (David Liu)

Cell Death and Disease (2016) 7, e2246; doi:10.1038/cddis.2016.157, Published online 2 June 2016