PPM-18, an Analog of Vitamin K, Induces Autophagy and Apoptosis in Bladder Cancer Cells Through ROS and AMPK Signaling Pathways

Abstract

PPM-18, identified as a novel analog of vitamin K, has been reported to play a critical role in the suppression of seizures. However, the concerns that whether PPM-18, like vitamin K, exerts anticancer activity remain to be further investigated. Here, we found that PPM-18 remarkably suppressed the proliferation and induced apoptosis in bladder cancer cells. Furthermore, a significant autophagic effect of PPM-18 on bladder cancer cells was also demonstrated, which profoundly promoted apoptotic cell death. Mechanistically, PPM-18 activated AMP-activated protein kinase (AMPK), whereas it repressed PI3K/AKT and mTORC1 pathways in bladder cancer cells. Inhibition of AMPK markedly relieved PPM-18–induced autophagy and apoptosis, indicating that PPM-18 is able to induce autophagy and apoptosis in bladder cancer cells via AMPK activation. Moreover, reactive oxygen species (ROS) were notably accumulated in PPM-18–treated bladder cancer cells, and treatment with ROS scavengers not only eliminated ROS production but also abrogated AMPK activation, which eventually rescued bladder cancer cells from PPM-18–triggered autophagy and apoptotic cell death. In bladder cancer xenografts, the anticancer activities of PPM-18, including suppressing the growth of tumors and inducing autophagy and apoptosis in tumor cells, were also established. Collectively, this study was the first to demonstrate the anticancer effect of PPM-18 on bladder cancer cells in vitro and in vivo through eliciting autophagy and apoptosis via ROS and AMPK pathways, which might provide new insights into the potential utilization of PPM-18 for future bladder cancer treatment.

The role of fat‐soluble vitamins in efferocytosis

“…It was also demonstrated that PPM‐18 decreased the expression of BCL‐2 in T24 and EJ cells while increasing the expression of BAX in T24 and EJ cells sequentially. These findings imply that PPM‐18 can cause bladder cancer cells to undergo mitochondria‐associated apoptosis 96 . Vitamin K2, also known as menaquinone‐4 (MK‐4), is an essential activator of bone mineralization in human osteoblasts and prevents bone osteoclastogenesis by causing osteoclast death 97 .…”

“…These findings imply that PPM-18 can cause bladder cancer cells to undergo mitochondria-associated apoptosis. 96 Vitamin K2, also known as menaquinone-4 (MK-4), is an essential activator of bone mineralization in human osteoblasts and prevents bone osteoclastogenesis by causing osteoclast death. 97 According to reports, MK-4 can lead to apoptosis in different types of tumor cells.…”

Vitamin K Contribution to DNA Damage—Advantage or Disadvantage? A Human Health Response

“…The anti-cancer potential of vitamin K has been the subject of research for several decades; its findings indicate that vitamin K (especially K2 and K3) can inhibit various types of cancer cells (ovarian cancer, leukemia, bladder cancer, hepatocellular carcinoma) through the induction of apoptosis or autophagy. The quinone moiety is present in the chemical structure of many cancer chemotherapeutic drugs such as anthracyclines daunorubicin, doxorubicin, mitoxantrone, or banoxantrone [ 94 , 95 , 96 , 97 , 98 ].…”

Interactions between Dietary Micronutrients, Composition of the Microbiome and Efficacy of Immunotherapy in Cancer Patients

“…Vitamin K influences cell proliferation by enhancing the expression of protein kinase A and inhibiting NF-κB by suppressing IκB kinase. The anti-tumor activity of the vitamin K analog—PPM-18 has also been demonstrated in a group of bladder cancer patients [ 136 ]. PPM-18 activated AMP-activated protein kinase (AMPK) and inhibited the PI3K/AKT and mTORC1 pathways in bladder cancer cells, inducing autophagy and apoptosis of cancer cells.…”