# Calliviminone A from Callistemon citrinus Induces PANC-1 Pancreatic Cancer Cell Death by Targeting the PI3K/Akt/mTOR Pathway

## TL;DR

A compound from Callistemon citrinus kills pancreatic cancer cells in low-nutrient conditions by targeting a key survival pathway.

## Contribution

Calliviminone A shows potent anti-austerity activity against pancreatic cancer cells by inhibiting the PI3K/Akt/mTOR pathway.

## Key findings

- Calliviminone A preferentially kills PANC-1 cells in nutrient-deprived conditions with a PC50 of 0.57 µM.
- The compound induces cell death and inhibits migration and colony formation in pancreatic cancer cells.
- Calliviminone A downregulates PI3K/Akt/mTOR pathway components, including inhibiting Akt and p-Akt activation.

## Abstract

Pancreatic cancer cells exhibit a remarkable ability to tolerate nutrient deprivation, a phenomenon termed “austerity,” which enables their survival within the hypovascular tumor microenvironment. Conventional anticancer therapies frequently fail to effectively target these resilient neoplastic cells, posing a significant challenge to the therapeutic management of pancreatic cancer. Consequently, targeting austerity, the ability of cancer cells to tolerate nutrient starvation, represents a promising anti-austerity strategy for developing novel pancreatic cancer therapeutics. In this study, we investigated calliviminone A (CVM-A), a phloroglucinol–meroterpenoid isolated from Callistemon citrinus leaves, for its anti-austerity activity against PANC-1 human pancreatic cancer cells. Calliviminone A exhibited potent preferential cytotoxicity in nutrient-deprived medium (NDM) with a PC50 of 0.57 µM, while showing minimal toxicity in nutrient-rich Dulbecco’s Modified Eagle’s medium (IC50 = 45.2 µM), indicating a favorable therapeutic index. Real-time live-cell imaging revealed that CVM-A induced significant morphological changes, including cell shrinkage and membrane blebbing, leading to cell death within 24 h of NDM. Furthermore, under normal nutrient conditions in Dulbecco’s Modified Eagle’s Medium (DMEM), CVM-A significantly inhibited PANC-1 cell migration (up to 47% reduction at 20 µM) and colony formation (over 80% suppression at 25 µM), suggesting its antimetastatic potential. Western blot studies demonstrated that CVM-A downregulated key survival components of the PI3K/Akt/mTOR signaling pathway, completely inhibiting Akt and p-Akt at 2.5 µM in NDM, and suppressing insulin-induced Akt activation. These findings highlight CVM-A as a promising lead compound for developing novel anticancer therapies that target the adaptive survival mechanisms and metastatic potential of pancreatic cancer in nutrient-deprived microenvironments.