“Development of anti-tumor drug precursor that simultaneously targets
heterogeneous tumor microenvironments”
Results by Professors Jong Seung Kim and Sung-Gil Chi’s group featured on front cover of JACS
▲ Top row from left: Dr. Amit Sharma, Dr. Min-Goo Lee and Dr. Miae Won;
bottom row from left: Dr. Seyoung Koo, Professor Sung-Gil Chi and Professor Jong Seung Kim
An anticancer precursor drug delivery technology that can overcome the limitations of conventional anticancer therapies, such as chemical and targeted anticancer drugs, was developed by a Korean research group.
The joint research team, consisting of Professor Jong Seung Kim of the Department of Chemistry, College of Science, and Professor Sung-Gil Chi, Dr. Amit Sharma, Dr. Min-Goo Lee, Dr. Miae Won and Dr. Seyoung Koo of the Department of Life Sciences, College of Life Science and Biotechnology, announced: “We have developed a novel anticancer target therapy that simultaneously activates drugs in heterogeneous tumor microenvironments to reduce the side effects of the existing anticancer drugs and maximize their anticancer effects.” Accordingly, there is anticipation concerning utilizing this new method of developing anticancer treatment technologies.
Cancer is a dynamic disease, and it acquires heterogeneity during its progression. Tumor heterogeneity refers to the different biological characteristics of tumor cells in different tumors of the same kind (inter-tumor) or within the same tumor (intra-tumor). It is revealed by the accumulation of various factors involved in oncogenesis, tumor proliferation, metabolism and gene expression. The genetic variation induces the expression of different proteins depending on the tumor cells, resulting in different cytological characteristics, such as those related to the key energy metabolism process of the cells. Tumor heterogeneity is drawing attention as one of the causes of tumor recurrence because it prevents all-at-once treatments of different tumor cells via a single anticancer therapy.
The various genetic variations and gene damage that happen during the oncogenesis and malignant progression and the cell duplication and division that indiscriminately occur under these abnormal conditions result in the overexpression of reactive oxygen species. The accumulation of oxidative stress generally causes cell apoptosis. However, tumor cells overexpress an antioxidant system that can neutralize the oxidative stress to maintain a balance in the oxidative/reductive environment for their survival. Therefore, ironically, a tumor includes a heterogeneous environment where the tumor cells that have a higher oxidative stress than that of normal cells coexist with those that have an overexpressed antioxidant system.
The compound used in the present study consists of an anticancer drug (SN-38), a cyclooxygenase-2 (COX-2) inhibitor and a drug precursor that is activated by hydrogen peroxide (H2O2), a type of reactive oxygen species, and by glutathione (GSH), a representative antioxidant system. Therefore, the compound used in the study has the capacity to not only selectively accumulate in colon cancer cells to deliver the drug while avoiding normal cells but also to be activated in heterogeneous tumor microenvironments, including oxidative/reductive stress, where the drug is simultaneously released, maximizing its anticancer effects. The study also showed that the compound inhibited COX-2, thus reducing the inflammatory responses in the tumor and enhancing the activation of normal immune functions.
The heterogeneous tumor-targeting anticancer drug precursor developed in the present study was injected into a mouse tumor model prepared by transplanting human colon cancer cells. The results showed that tumor volume was reduced by more than 40 times compared to the control group and by about two times compared to a group treated with SN-38. No specific side effects of the drug were found.
The joint research team successfully developed a new anticancer targeted drug with improved colon cancer-selective drug efficacy by investigating tumor heterogeneity and synthesizing an anticancer precursor allowing for simultaneous targeting of the heterogenous tumor microenvironments. Professors Kim and Chi stated: “Through the heterogeneous tumor-targeting anticancer drug precursor, we can understand the environmental differences between cancer cells and overcome the therapeutic limitations related to tumor heterogeneity and variety. The treatment strategy based on selective anticancer targeting drugs with improved therapeutic efficiency will provide a great help to the development of anticancer drugs in the future.”
Their results were published on October 2, 2019, in the Journal of the American Chemical Society (JACS), a prominent international chemistry journal, and the article was selected for the front cover of the October issue.
*Title of article: Targeting Heterogeneous Tumors Using a Multifunctional Molecular Prodrug
▲ (Figure description) Development of anticancer precursor simultaneously targeting heterogeneous tumor microenvironments.
1) Selected as the front cover article of the October 2019 issue of JACS.
2) The anticancer drug is simultaneously activated in the oxidative stress environment where hydrogen peroxide is overexpressed and in the reductive stress environment where GSH is overexpressed, inducing apoptosis of cancer cells. The developed precursor targets colon cancer via the COX-2 inhibitor and increases the anticancer effects by inhibiting the production of inflammatory substances such as VEGF, IL-6 and TNF-α.