Abstract Cancer remains one of the most complex and challenging diseases because of its heterogeneity and the ability of tumor cells to become resistant to the treatment. Among various cancers, glioblastoma and colon cancers are the most prevalent and deadliest cancer worldwide. It is responsible for significant burden on the healthcare system and affects millions of lives every year. Despite advancement in cancer treatment, including chemotherapy, radiotherapy, targeted therapies, and immunotherapy, achieving complete remission remains challenging that contributes to the poor prognosis of glioblastoma patients. One promising area of research involves a group of enzymes called dipeptidyl peptidases DPPs, a family of serine proteases which are known to regulate various biological processes, including immune function, metabolism, and cancer progression. Dipeptidyl peptidases DPPs, particularly DPP8, have emerged as promising molecular targets in cancer therapy. This study investigates the mechanistic role of DPP8 inhibition in glioblastoma and colorectal cancer cells. Cell viability was assessed using trypan blue and CCK8 assays, while apoptosis was evaluated via Giemsa staining, DNA fragmentation, Annexin V FITC PI, and cell cycle analysis. Flow cytometry revealed increased ROS production, loss of mitochondrial membrane potential and intracellular calcium level following treatment. Western blotting showed enhanced expression of apoptosis-related proteins 24 hr after treatment with DPP8 inhibitor. These findings suggest that DPP8 inhibition induce mitochondria mediated apoptotic pathways and may serve as a novel therapeutic strategy, offering potential for targeted and personalized cancer treatment approaches. Citation Format: Paras Jawaid, Mati Ur Rehman, Azhar Hussain Rajabali, Ather Enam. Advancing cancer treatment through targeting dipeptidyl peptidase 8 an innovative strategy for overcoming resistance abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 551.
Jawaid et al. (Fri,) studied this question.