Mitochondria determine the efficacy of anticancer agents that interact with DNA but not the cytoskeleton

Our plain-English summary of Mitochondria determine the efficacy of anticancer agents that interact with DNA but not the cytoskeleton, by K. Hara, E. Kasahara, N. Takahashi, et al (The Journal of Pharmacology and Experimental Therapeutics, 2011).

The study

• Authors: K. Hara, E. Kasahara, N. Takahashi, M. Konishi, J. Inoue, M. Jikumaru, S. Kubo, H. Okamura, E. Sato, M. Inoue
• Journal: The Journal of Pharmacology and Experimental Therapeutics
• Published: 2011;337(3):838-45
• Cited by: 23 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Although chemotherapy is an important method for the treatment of patients with cancer, its efficacy is limited because of different sensitivities of tumor cells to anticancer agents and/or side effects on normal tissues. The present work demonstrates that mitochondria play a crucial role in the apoptosis of cancer cells induced by anticancer agents that interact with DNA but not with the cytoskeleton. Agents that interact with DNA selectively enhanced generation of reactive oxygen species (ROS) in mitochondria, released cytochrome c, and activated caspase-9 and caspase-3 to induce apoptosis of mesothelioma H2052 cells but not their ρ(0) cells, which lack mitochondrial DNA (mtDNA). The sensitivity of a variety of cells to the agents showed positive correlation with the amounts of their mitochondria. In contrast, agents that selectively affect the cytoskeleton activated caspase-8 and caspase-3 and equally induced apoptosis of both H2052 and their ρ(0) cells by a mitochondria-independent mechanism. The results suggest that mtDNA is a potential target for the anticancer agents that interact with DNA to induce ROS-dependent apoptosis of cancer cells, whereas agents that affect the cytoskeleton induce cell death by a mitochondria- and ROS-independent mechanism. The present observation is important for the selection of medicine for chemotherapy of patients with cancer.

In plain English

This was a laboratory study of cancer cells grown in culture. It did not study asbestos exposure or people. The authors, based in Japan, tested nine anticancer drugs on a human mesothelioma cell line called H2052. They also tested a version of those cells made to lack mitochondrial DNA. Mitochondria, the cell's energy-producing structures, carry their own DNA. Six of the drugs act on DNA (cisplatin, bleomycin, doxorubicin, methotrexate, busulfan, fluorouracil). Three act on the cell's internal skeleton (paclitaxel, colchicine, vinblastine). In H2052 cells, the DNA-acting drugs increased reactive oxygen species, which are chemically reactive molecules. They also released cytochrome c from mitochondria and activated caspase-9. They killed the original H2052 cells more than the H2052-derived cells lacking mitochondrial DNA. A scavenger of these reactive molecules reduced the killing by the DNA-acting drugs. The skeleton-acting drugs did not raise reactive oxygen species, activated caspase-8 instead, and killed both cell types equally. Across various cancer cell lines, cells with more mitochondria were more sensitive to the DNA-acting drugs. The authors concluded that mitochondria play a crucial role in cell death caused by DNA-acting drugs but not skeleton-acting drugs.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (in vitro) cell-culture experiment, with additional tests on mitochondria isolated from mouse liver
• Who was studied: Human mesothelioma cell lines H2052 and H2452, plus H2052-derived cells depleted of mitochondrial DNA, and other cancer and cell lines (HeLa, HepG2, HL-60, LLC, HEK293, B16); mitochondria isolated from livers of male C57BL6/J mice. Work was done in Osaka, Japan; no human subjects.
• Exposure: Anticancer drugs, not asbestos. Agents acting on DNA: cisplatin, bleomycin, doxorubicin, methotrexate, busulfan, fluorouracil. Agents acting on the cytoskeleton: paclitaxel, colchicine, vinblastine. Cells were treated for 24 hours, some with the superoxide scavenger Mn-TBAP.
• Main results:
  • In H2052 cells, cisplatin increased reactive oxygen species over time but paclitaxel did not, although both killed cells in a dose-dependent way.
  • In H2052 cells, the cytoskeleton-acting agents (paclitaxel, colchicine, vinblastine) did not induce reactive oxygen species, whereas the DNA-acting agents strongly enhanced it.
  • In H2052 cells, the scavenger Mn-TBAP suppressed cell death from DNA-acting agents but not from cytoskeleton-acting agents.
  • In H2052 cells, DNA-acting agents released cytochrome c from mitochondria into the cell fluid; cytoskeleton-acting agents did not.
  • The original H2052 mesothelioma cells were more sensitive to all DNA-acting agents than the H2052-derived cells lacking mitochondrial DNA.
  • DNA-acting agents increased reactive oxygen species in H2052 cells but not in the cells lacking mitochondrial DNA.
  • DNA-acting agents activated caspase-9, not caspase-8, in H2052 cells.
  • Cytoskeleton-acting agents activated caspase-8, not caspase-9, in both H2052 cells and the cells lacking mitochondrial DNA.
  • Across the cells tested, a greater amount of mitochondria was associated with greater sensitivity to DNA-acting agents.
  • Sensitivity to cytoskeleton-acting agents was not associated with the amount of mitochondria.
  • In mitochondria isolated from mouse liver, neither cisplatin nor paclitaxel induced reactive oxygen species under the conditions tested.
• The authors' conclusion: The authors concluded that mitochondria play a crucial role in cell death induced by DNA-acting anticancer agents but not cytoskeleton-acting agents. They also stated that fewer mitochondria in cancer cells underlies, at least in part, multidrug resistance.
• Limitations the authors state:
  • The authors stated that their explanation for the slow onset of reactive oxygen species and membrane-potential loss needs further study.
  • The authors stated that the reason their paclitaxel findings differ from other studies showing mitochondrial involvement remains unknown.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Chemotherapy, Apoptosis, Reactive Oxygen Species (ROS), Mesothelioma.

Related studies

• Mitochondria-targeted Ogg1 and aconitase-2 prevent oxidant-induced mitochondrial DNA damage in alveolar epithelial cells — S.J. Kim, P. Cheresh, et al. (2014)
• Pemetrexed induces apoptosis in malignant mesothelioma and lung cancer cells through activation of reactive oxygen species and inhibition of sirtuin 1 — K.E. Hwang, Y.S. Kim, et al. (2015)
• Licochalcone A induces apoptosis in malignant pleural mesothelioma through downregulation of Sp1 and subsequent activation of mitochondria-related apoptotic pathway — K.H. Kim, G. Yoon, et al. (2015)
• Mitochondria-derived reactive oxygen species drive GANT61-induced mesothelioma cell apoptosis — C.B. Lim, C.M. Prêle, et al. (2015)
• The Role of Mitochondrial DNA in Mediating Alveolar Epithelial Cell Apoptosis and Pulmonary Fibrosis — S.J. Kim, P. Cheresh, et al. (2015)
• Manumycin A induces apoptosis in malignant pleural mesothelioma through regulation of Sp1 and activation of the mitochondria-related apoptotic pathway — K.H. Kim, J.I. Chae, et al. (2016)

Browse return to medical research.