Lysosome‑targeted drug combination induces multiple organelle dysfunctions and non‑canonical death in pancreatic cancer cells

• Published in: Oncology reports Vol. 47; no. 2; p. 1
• Main Authors: Suzuki, Sumire, Ogawa, Masato, Miyazaki, Masaya, Ota, Kohki, Kazama, Hiromi, Hirota, Ayako, Takano, Naoharu, Hiramoto, Masaki, Miyazawa, Keisuke
• Format: Journal Article
• Language: English
• Published: Greece Spandidos Publications 01.02.2022; Spandidos Publications UK Ltd; D.A. Spandidos
• Subjects: Aminopyridines - pharmacology; Antimitotic agents; Antineoplastic agents; Antineoplastic Agents - pharmacology; Apoptosis; Autophagy; Benzimidazoles - pharmacology; Biotechnology industry; Cancer cells; Carcinoma, Pancreatic Ductal - drug therapy; Cell cycle; Cell death; Cell Line, Tumor; Chemotherapy; Dehydrogenases; Drug Synergism; Drug therapy, Combination; Drugs; Endoplasmic Reticulum Stress - drug effects; Epidermal growth factor; Experiments; Fingolimod Hydrochloride - pharmacology; Health aspects; Humans; Hydroxychloroquine - pharmacology; Inhibitor drugs; Japan; Kinases; Laboratories; Lapatinib - pharmacology; Lung cancer; Lysosomes - drug effects; Mortality; Mutation; Pancreatic cancer; Pancreatic Neoplasms - drug therapy; Proteins; Reagents; Scientific equipment and supplies industry; Sphingosine; Sphingosine 1 Phosphate Receptor Modulators - pharmacology; Standard deviation; Targeted cancer therapy; United States; United States; Japan; non‑canonical cell death; hydroxychloroquine; fingolimod; abemaciclib; lapatinib; lysosomal membrane permeabilization; calcium homeostasis; pancreatic cancer cells; endoplasmic reticulum stress; mitochondrial depolarization; lysosome‑targeted drug combination
• DOI: 10.3892/or.2021.8251
• ISSN: 1021-335X

Pancreatic cancer is one of the leading causes of cancer‑related mortality and has the lowest 5‑year survival rate. Therefore, novel strategies are urgently required to treat pancreatic cancer. Pancreatic ductal adenocarcinoma (PDAC) cells rely on enhanced lysosomal function for survival and proliferation to facilitate the degradation of contents accumulated via autophagy and macropinocytosis. Previously, we have reported that the combination of epidermal growth factor receptor/HER2 inhibitor lapatinib and sphingosine analog fingolimod (FTY720) confers a significant cytostatic effect in lung cancer cells. In the present study, the combined effects of these drugs on PDAC cell lines, BxPC‑3, KP‑4, PANC‑1 and MIA PaCa‑2, were examined. It was observed that FTY720 enhanced the lapatinib‑induced cytotoxic effect and caused non‑canonical and lysosome‑dependent death in PDAC cells. Lapatinib and FTY720 induced lysosomal swelling and inhibited lysosomal acidification. Combination treatment with lapatinib and FTY720 increased lysosomal membrane permeability, induced mitochondrial depolarization, induced endoplasmic reticulum stress and disturbed intracellular calcium homeostasis. Additionally, the cytotoxic effect of lapatinib was enhanced by hydroxychloroquine or the CDK4/6 inhibitor abemaciclib, both of which induce lysosomal dysfunction. Collectively, these results indicated that the lysosome‑targeted drug combination induces multiple organelle dysfunction and exerts a marked cytotoxic effect in PDAC cells.