Energetic heavy ions overcome tumor radioresistance caused by overexpression of Bcl-2

Hamada, Nobuyuki; Hara, Takamitsu; Omura-Minamisawa, Motoko; Funayama, Tomoo; Sakashita, Tetsuya; Sora, Sakura; Yokota, Yuichiro; Nakano, Takashi; Kobayashi, Yasuhiko

doi:10.1016/j.radonc.2008.02.013

Cited by 33 publications

(21 citation statements)

References 36 publications

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“…(25)(26)(27) The LET at the cell surface was calculated according to the kinetic energy loss, assuming water equivalence. Dose (Gy) was calculated as fluence (ion particles/ cm 2 ) × LET (keV/μm) × 1.6 × 10 -9 .…”

Section: Methodsmentioning

confidence: 99%

Heavy‐ion‐induced bystander killing of human lung cancer cells: Role of gap junctional intercellular communication

Harada¹,

Nonaka²,

Hamada

et al. 2009

Cancer Science

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It is thought that heavy-ion radiation therapy is a promising modality of cancer therapy that can deliver higher biological effects on tumors than conventional X-ray radiation therapy, and may also conserve the function of normal organs because of its excellent dose distribution.(1) Recently, excellent clinical results were reported in the treatment of lung cancer, prostate cancer, cancer of the head and neck, and malignant tumors of bone and soft tissue.(2) Heavy-ion has high linear energy transfer (LET) with increased relative biological effectiveness (RBE). However, the possible mechanism of increasing cell killing in heavyion therapy is not fully understood. Previous studies have demonstrated that the induction of cell killing of non-irradiated cells by adjacent cells that are directly irradiated by heavy-ions is considered to play an important role in radiation-induced cell death, not only in tumors but also in normal organs. This phenomenon is termed the "bystander effect", and was reported by Nagasawa and Little in 1992.(3) They reported that increased sister chromatid exchanges were observed in more than 30% of cells when less than 1% of the nuclei of cultured cells were actually traversed by an α-particle in Chinese hamster ovary cells. It has been proposed that the mediating mechanism involves secreted soluble factors, (4)(5)(6) an increase in oxidative stress,plasma membrane-bound lipid rafts, (8) and gap junctional intracellular communication (GJIC). (4,7,(9)(10)(11)(12)(13) Gap junctions are membrane channels that connect the cytoplasm of cells and allow direct exchange of small molecules and ions between adjacent cells. GJIC is essential for the maintenance of tissue homeostasis and proliferation and the regulation of embryonic development and differentiation, and it plays a key role in induction of the bystander effect. (14)(15)(16)(17) Here, bystander killing of cells by heavy-ion irradiation was investigated, focusing on the involvement of GJIC on cell survival, to clarify the underlying mechanisms of the bystander effect in a human lung cancer cell line in vitro. Materials and MethodsCell cultures. A549 (a human lung cancer cell line with wild-type p53) was obtained from the Cell Resource Center for Biomedical Research at the Institute of Development, Aging and Cancer, Tohoku University, Japan. Cells were cultured in RPMI-1640 medium (Immuno-Biological Laboratories, Takasaki, Japan) supplemented with 10% fetal calf serum (PAA Laboratories, Pasching, Austria). Two days prior to irradiation experiments, 5 × 10 5 and 5 × 10 4 cells were inoculated into a specially designed 35-mm microbeam dish that was constructed as previously described, (18) to prepare confluent cultures and sparsely populated cultures, respectively. Unless otherwise described, all cell cultures were maintained at 37°C in a humidified atmosphere of 5% CO 2 in air. The size of the cell nucleus and the whole cells was determined to be 14.6 ± 4.3 and 106 ± 24.9 μm 2 , respectively. Drug treatment. Prior to irradiation, cells were p...

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Section: Methodsmentioning

confidence: 99%

Heavy‐ion‐induced bystander killing of human lung cancer cells: Role of gap junctional intercellular communication

Harada¹,

Nonaka²,

Hamada

et al. 2009

Cancer Science

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“…We previously showed that Bcl-2 cells express ninefold higher levels of Bcl-2 proteins and are more resistant to γ-rays than Neo cells (Hara et al, 2005;Hamada et al, 2008e), and that there is no statistically significant difference in population doubling time and plating efficiency between sham-irradiated Neo and Bcl-2 cells . To assess the impact of Bcl-2 overexpression on the bystander effect for the survival, 10 particles was delivered to each of 1, 5 and 25 sites in situations whereby particle(s) traversed only 0.0002, 0.0009 and 0.005% of the cells, respectively.…”

Section: Impact Of Bcl-2 Overexpression On the Bystander Responsementioning

confidence: 99%

Heavy-Ion Microbeam Irradiation Induces Bystander Killing of Human Cells

et al. 2008

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Significant evidence indicates that ionizing radiation causes biological effects in nonirradiated bystander cells having received signals from directly irradiated cells. There is little information available hitherto as to the bystander effect of energetic heavy ions; however, our previous work has shown that in confluent cultures of normal human fibroblast AG01522 cells, targeted exposure of 0.0003% of cells to microbeams of 18.3 MeV/u 12 C (103 keV/µm) and 13.0 MeV/u 20 Ne (375 keV/µm) ions can similarly cause almost 10% decreases in the clonogenic survival, and twofold increments in the incidence of apoptosis whose temporal kinetics varies between irradiated and bystander cells. Using this experimental system, here we further report that bystander responses of AG01522 cells to 17.5 MeV/u 20 Ne ions (294 keV/µm) are consistent with those to 18.3 MeV/u 12 C and 13.0 MeV/u 20 Ne ions. We also demonstrate that such bystander-induced reductions in the survival are less pronounced and occur independently of Bcl-2 overexpression in human cervical cancer HeLa cells.

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“…Cells at passage 9 were seeded at 200 cells/cm 2 on 6-cm dishes, and incubated at 37˚C in a humidified atmosphere of 5% CO 2 in air, at which time irradiation was carried out at room temperature as mentioned (Hamada et al, 2008b(Hamada et al, , 2008c(Hamada et al, , 2008d. In brief, cells were exposed to 60 Co γ-rays (0.2 keV/µm) at a dose rate of 1 Gy/min.…”

Section: Cell Culture and Irradiationmentioning

confidence: 99%

Exposure of Normal Human Fibroblasts to Heavy-Ion Radiation Promotes Their Morphological Differentiation

et al. 2008

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Here we investigated the potential impact of energetic heavy ions on fibroblast differentiation. The differentiation pattern was morphologically determined at days 3 and 5 after exposure to graded dose of γ-rays (0.2 keV/µm) or carbon ions (18.3 MeV/u, 108 keV/µm). The cells irradiated with higher doses progressed toward later differentiation stages as time goes postirradiation, but underwent fewer cell divisions. Thus, radiation exposure accelerated morphological differentiation, for which carbon ions were more effective than γ-rays. The relative biological effectiveness of carbon ions for differentiation was higher than that for the clonogenic survival, and this was the most case for terminally differentiated cells that may not divide any more. The results are suggestive of the distinct mechanism underlying inactivation of clonogenic potential between the radiation quality, such that the contribution of the differentiation to heavy ion-induced reductions in the survival is greater than to those induced by photons. Such accelerated differentiation could be a protective mechanism that minimizes further expansion of aberrant cells.

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Energetic heavy ions overcome tumor radioresistance caused by overexpression of Bcl-2

Cited by 33 publications

References 36 publications

Heavy‐ion‐induced bystander killing of human lung cancer cells: Role of gap junctional intercellular communication

Heavy‐ion‐induced bystander killing of human lung cancer cells: Role of gap junctional intercellular communication

Heavy-Ion Microbeam Irradiation Induces Bystander Killing of Human Cells

Exposure of Normal Human Fibroblasts to Heavy-Ion Radiation Promotes Their Morphological Differentiation

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