Open Access

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

  • Authors:
    • Sumire Suzuki
    • Masato Ogawa
    • Masaya Miyazaki
    • Kohki Ota
    • Hiromi Kazama
    • Ayako Hirota
    • Naoharu Takano
    • Masaki Hiramoto
    • Keisuke Miyazawa
  • View Affiliations

  • Published online on: December 24, 2021     https://doi.org/10.3892/or.2021.8251
  • Article Number: 40
  • Copyright: © Suzuki et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

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.
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February-2022
Volume 47 Issue 2

Print ISSN: 1021-335X
Online ISSN:1791-2431

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Spandidos Publications style
Suzuki S, Ogawa M, Miyazaki M, Ota K, Kazama H, Hirota A, Takano N, Hiramoto M and Miyazawa K: Lysosome‑targeted drug combination induces multiple organelle dysfunctions and non‑canonical death in pancreatic cancer cells. Oncol Rep 47: 40, 2022
APA
Suzuki, S., Ogawa, M., Miyazaki, M., Ota, K., Kazama, H., Hirota, A. ... Miyazawa, K. (2022). Lysosome‑targeted drug combination induces multiple organelle dysfunctions and non‑canonical death in pancreatic cancer cells. Oncology Reports, 47, 40. https://doi.org/10.3892/or.2021.8251
MLA
Suzuki, S., Ogawa, M., Miyazaki, M., Ota, K., Kazama, H., Hirota, A., Takano, N., Hiramoto, M., Miyazawa, K."Lysosome‑targeted drug combination induces multiple organelle dysfunctions and non‑canonical death in pancreatic cancer cells". Oncology Reports 47.2 (2022): 40.
Chicago
Suzuki, S., Ogawa, M., Miyazaki, M., Ota, K., Kazama, H., Hirota, A., Takano, N., Hiramoto, M., Miyazawa, K."Lysosome‑targeted drug combination induces multiple organelle dysfunctions and non‑canonical death in pancreatic cancer cells". Oncology Reports 47, no. 2 (2022): 40. https://doi.org/10.3892/or.2021.8251