JP6889458B2 - 細胞増殖抑制剤 - Google Patents
細胞増殖抑制剤 Download PDFInfo
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- JP6889458B2 JP6889458B2 JP2016154949A JP2016154949A JP6889458B2 JP 6889458 B2 JP6889458 B2 JP 6889458B2 JP 2016154949 A JP2016154949 A JP 2016154949A JP 2016154949 A JP2016154949 A JP 2016154949A JP 6889458 B2 JP6889458 B2 JP 6889458B2
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Description
[1]可溶化メラニン又は分散化メラニンを有効成分として含む、細胞の増殖抑制剤。
[2]可溶化メラニンがHepes溶解メラニンである、[1]に記載の増殖抑制剤。
[3]分散化メラニンの平均粒子径が70nm〜130nmである、[1]に記載の増殖抑制剤。
[4]分散化メラニンがレーザーアブレーションによって得られる、[3]に記載の増殖抑制剤。
[5]細胞が腫瘍細胞である、[1]〜[4]のいずれか一項に記載の増殖抑制剤。
[6]がんの治療に使用される、[5]に記載の増殖抑制剤。
[7]抗がん剤が併用される、[6]に記載の増殖抑制剤。
(1)細胞と培養条件
ラット好塩基球性白血病細胞株(RBL-2H3)、ヒトがん細胞株として、子宮頸部類上皮がん(HeLa)、乳がん(MCF-7)、肝細胞がん(HepG2)、急性T細胞性白血病細胞(Jurkat)、マウスメラノーマ細胞株(B16F10)を用いた。
メラニンは市販の合成メラニン(MP biomedicals、Sigma)を用いた。細胞生存率測定試薬として、セルカウンティングキット8(Dojindo)を用いた。
(i) レーザーアブレーション処理メラニン(微粒子分散化メラニン)
合成メラニンを0.1wt%となるよう滅菌済みPBS中に懸濁し、以下のレーザー照射条件にて分散メラニン溶液を取得した。
波長1064nm, FWHM 5ns, 1.2J/cm2・pulse, 10Hz, 2.5mmφ, 60分間
Hepes(Sigma-Aldrich)を超純水に溶解し、ポアサイズ0.22μmの親水性PVDF膜(Merck Millipore Corporation)を用いてフィルターろ過滅菌した(Hepesバッファー)。これに合成メラニンを50mg/mlとなるよう溶解し、室温にて保存した。
96ウェルプレートに2×105個/ウェルとなるように細胞を播種した。37℃にて24時間培養後、コンフルエント状態となっていることを確認し、各種濃度のメラニンを投与した。細胞死誘導剤としてスタウロスポリン(STPO)、もしくはヒ素を投与した。さらに37℃にて24時間培養後、セルカウンティングキット8誌薬にて細胞生存率を計測した。
96ウェルプレートに2×104個/ウェルとなるように細胞を低密度で播種すると同時に、各種濃度のメラニンを投与した。細胞死誘導剤として、STPO、もしくはヒ素を使用した。投薬後、37℃にて24時間培養し、セルカウンティングキット8試薬にて細胞生存率を計測した。
薬液を持続的に体内へ注入できる浸透圧ポンプ(アルゼット浸透圧ポンプ、室町機械)に、Hepes溶解メラニンを18.9mg/mlの濃度で注入した。浸透圧ポンプは0.11μl/hrで薬液を排出することから、メラニン投与量は50μg/マウス/日となる。ヌードマウス(BALB/c Slc-nu/nu, 9週齢, 日本エスエルシー)にメラニンもしくは対照としてHepesを注入した浸透圧ポンプを外科的に皮下へ埋め込んだ。翌日、マウスメラノーマ細胞株B16F10を、浸透圧ポンプ近傍約1cmの部位に2×105個注射し、その後20日までの腫瘍の体積を経時的に計測した。腫瘍の体積は下記近似式を用いて算出した(坂上隆ら. 1990. ラットRF加温装置とそれを用いた腫瘍増殖抑制効果について:RF加温・温熱化学療法に関する実験的研究 (第1報). 日本ハイパーサーミア学会誌 6: 473-490.)。
V = (W2×L)/2 (V:体積、W:短径、L:長径)
24ウェルマイクロプレートに1×106個/ウェルとなるようにヒト乳がん細胞株(MCF-7)を播種した。Hepes可溶化チロシンを投与し、24時間後、細胞を70%エタノールで固定した。Propidium Iodide染色液にてDNAを染色し、フローサイトメーター(FACS Canto, BD Biosciences)を用いてデータを取得した。細胞周期は解析ソフトウェア(FlowJo)を用いて解析した。
3×106/ml (E-MEM培地)のHepG2細胞を播培養ディッシュに播種し、24時間培養した。37℃のE-MEM培地に希釈した種々の濃度のメラニンを細胞へ24時間処理後した。PBSで3回洗浄し、20mM Tris-HCl (pH7.5), 150mM NaCl, 1mM EDTA, 1% Triton X-100, 1mM PMSF, プロテアーゼ阻害剤カクテル(Sigma)およびホスファターゼ阻害剤カクテル(Sigma)を含む細胞溶解緩衝液100μl中で溶解し、15,000×gの遠心で清澄化させた細胞溶解液のタンパク質濃度測定後、4×SDSサンプル緩衝液とともに煮沸した。タンパク質量として10〜20μgの試料をSDS-PAGEで分離し、PVDF膜に転写後、特異的抗体で目的のタンパク質バンドを検出した。
(1)微粒子分散化および完全可溶化メラニン溶液の創製
細胞増殖を抑制する本体がメラニンである可能性が考えられたため、市販の合成された精製メラニンをRBL-2H3細胞に投与する実験を創案した。しかしながら、市販の合成メラニンは水のほか、様々な有機溶媒に不溶であり、顔料的な性質をもつ色素であることが知られている(佐藤健. 1998. イカスミ色素の最近の応用 (特集 色素と健康--食品活性成分の秘密). Food style 21 2: 80-81.)。そこで、レーザーアブレーション技術により、均一な分散溶液を得た。得られた微粒子分散化メラニン溶液は、電子顕微鏡観察によれば粒子径が70〜130nmであることが判明した(図3A)。一方、様々な生化学的中性バッファーへの溶解を試みたところ、市販の合成メラニンは500mM、pH7.5のHepesバッファーに50mg/mlの濃度でほぼ完全に溶解することを始めて見出した(図3B)。また、可溶性メラニンの化学的合成法が公開されている(特許文献1)。この方法を参考にすると、反応初期物質がL-Dopaの場合、メラニン(ユーメラニン)が合成され、反応初期物質がL-Dopamineの場合、メラニン様物質を作製することができる(図4)。ユーメラニンの場合は重合したインドールユニットの2位の位置にカルボキシル基が存在し、メラニン様物質の場合はカルボキシル基が存在しない重合体が生成すると考えられる。可溶性メラニンを合成後、HepesもしくはH2Oに完全溶解したメラニンを取得した。以上、このようにして得られた水溶液中で均一性の高いメラニン、もしくはメラニン様物質溶液を、以後の実験に用いた。
コンフルエントとなったラット好塩基球性白血病細胞RBL-2H3に、各種濃度の微粒子分散化メラニン、もしくは細胞死誘導の陽性コントロールとして2.5μg/mlのスタウロスポリン(STPO)を処理し、24時間培養した。セルカウンティングキット8により生細胞を計測し、陰性コントロールの値を100%として細胞生存率を測定した。対照サンプルは50%PBSのEMEM培地を用いた。STPO処理ではほとんどの細胞が死滅したのに対し、微粒子分散化メラニンは少なくとも最大処理濃度0.5mg/mlまで細胞死誘導は認められなかった(図5A)。一方、RBL-2H3細胞を低密度でディッシュに播種すると同時に、各種濃度の微粒子分散化メラニン、もしくはSTPOを処理し、24時間培養後、セルカウンティングキット8により細胞の生存率を測定した。その結果、処理濃度0.062mg/ml〜0.5mg/mlまでにおいて、処理濃度依存性に細胞増殖が有意に抑制された(図5B)。
合成可溶性メラニン、もしくは合成可溶性メラニン様物質を500mMのHepesに溶解し、50mg/mlのストック溶液を準備した。コンフルエントとなったヒト肝がん由来細胞株HepG2に、各種濃度(0.062〜0.5mg/ml)の合成可溶性メラニン、もしくは合成可溶性メラニン様物質を処理し、24時間培養した。細胞死誘導の陽性コントロールとして1mMのヒ素を処理した。セルカウンティングキット8により生細胞を計測し、陰性コントロールの値を100%として細胞生存率を測定した。対照サンプルは5mMのHepes入りEMEM培地を用いた。ヒ素処理ではほとんどの細胞が死滅したのに対し、可溶性メラニン、可溶性メラニン様物質は、いずれも、少なくとも最大処理濃度0.5mg/mlまで細胞死誘導は認められなかった(図6A、B)。一方、HepG2細胞を低密度でディッシュに播種すると同時に、各種濃度の可溶性メラニン、もしくは可溶性メラニン様物質を処理し、24時間培養後、セルカウンティングキット8により細胞の生存率を測定した。その結果、可溶性メラニンでは処理濃度0.125mg/ml〜0.5mg/mlまでにおいて、可溶性メラニン様物質では処理濃度0.25mg/ml〜0.5mg/mlまでにおいて、処理濃度依存性に細胞増殖が有意に抑制された(図6C、D)。
市販のメラニンを500mMのHepesに溶解し、50mg/mlのストック溶液を準備した。このメラニンを用い、ヒト子宮頸がん細胞株(HeLa)、ヒト乳がん細胞株(MCF-7)、ヒトTリンパ球性白血病細胞株(Jurkat)に対する細胞毒性、および細胞増殖抑制効果を調べた。コンフルエントとなった各種がん細胞株に、各種濃度(0.031〜0.5mg/ml)のHepes溶解メラニンを処理し、24時間培養した。セルカウンティングキット8により生細胞を計測し、陰性コントロールの値を100%として細胞生存率を測定した。実験の結果、投与したHepes溶解メラニン濃度においては、いずれのがん細胞株においても細胞毒性は示されなかった。一方、これらの細胞株を低密度でディッシュに播種すると同時に、各種濃度のHepes溶解メラニンを処理し、24時間培養後、セルカウンティングキット8により細胞の生存率を測定した。その結果、HeLa、MCF-7細胞株においてはHepes溶解メラニンの処理濃度0.125mg/ml〜0.5mg/mlまでにおいて、Jurkat細胞株においては、Hepes溶解メラニンの処理濃度0.031mg/ml〜0.5mg/mlまでにおいて、それぞれ処理濃度依存性に細胞増殖が有意に抑制された(図7)。
市販のメラニンを500mMのHepesに溶解し、50mg/mlのストック溶液を準備した。まず、in vitroにおいて、Hepes溶解メラニンによるマウスメラノーマ細胞株B16F10に対する細胞増殖抑制効果を確認した。B16F10を低密度でディッシュに播種すると同時に、各種濃度のHepes溶解メラニンを処理し、24時間培養後、セルカウンティングキット8により細胞の生存率を測定した。実験の結果、Hepes溶解メラニンの処理濃度0.25mg/ml〜0.5mg/mlまでにおいて、処理濃度依存性に細胞増殖が有意に抑制された(図8A)。次に、Hepes溶解メラニンを浸透圧ポンプに注入してヌードマウスの皮下腹側部に移植した。翌日、マウスメラノーマ細胞株B16F10を皮下へ注射し、その後の腫瘍体積を計測した。実験の結果、Hepesメラニンを投与した群は、腫瘍の増大が有意に抑制された(図8B)。
メラニンによる細胞増殖抑制のメカニズムを調べるため、細胞周期解析を行った。ヒト乳がん細胞株MCF-7にHepes溶解メラニンを0.25mg/mlの濃度で48時間処理した。フローサイトメトリーによる細胞周期解析を行った結果、Hepes溶解メラニン処理によって、G0/G1期の細胞の割合がコントロールに比べて有意に上昇し、S期の細胞の割合が相対的に減少した(図9)。この結果から、メラニン処理によって細胞周期がG0/G1期で停止し、DNA合成期への進行が抑制されている可能性が示唆された。
G0/G1期にて細胞周期の進行が阻害されている可能性が示唆されたことから、有糸***の進行の指標であるヒストンH3のリン酸化を調べた。ヒト肝がん細胞株HepG2に対し、Hepes溶解メラニンを0.25もしくは0.5mg/mlの濃度で処理し、24時間培養した。可溶性タンパク質を抽出し、ウェスタンブロッティングにてヒストンH3とリン酸化ヒストンH3をそれぞれ検出した。実験の結果、ヒストンH3のリン酸化はHepes溶解メラニン処理濃度依存性に抑制された(図10)。これらの結果から、メラニンは有糸***過程の阻害に関与していることが強く示唆された。
メラニンは生物界に広く分布しており、生物種によって様々に利用されている。メラニンを医薬・生物学的に利用する試みは極めて少なく、人工合成メラニンによるHIV複製阻害(特表2001−512437号公報)、サイトカイン調製能(特表2001−512446号公報)、といった先行研究は存在するが、細胞増殖抑制を目的としたメラニンの利用・応用の報告は国内外を問わずなされていない。本研究では主に、株化がん細胞を対象として用い、固形がん、血球系がんを含む検討した全ての細胞株で、可溶化・微粒子分散化メラニンが明らかな細胞死誘導を起こさない濃度において、細胞増殖を効果的に抑制した。このことは、当該調整メラニンは正常細胞に重篤な障害を及ぼさない範囲で、細胞死は誘導せずとも異常増殖しているがん細胞の増殖を抑制し、がん患者の延命をもたらし得ることを示唆する。これまでに多種多様な抗がん剤が開発されており、多くは正常細胞にも障害を与え副作用を持ち併せるが、近年はがん細胞特異的な障害を引き起こす分子標的分子標的治療薬や、免疫監視機構の再活性化を誘導する抗体医薬が開発され奏功している。
Claims (7)
- Hepes溶解メラニン又は分散化メラニンを有効成分として含む、細胞の増殖抑制剤。
- Hepes溶解メラニンが、タンパク質成分を含まない難解性メラニンをHepesで可溶化したものである、請求項1に記載の増殖抑制剤。
- Hepes溶解メラニンの分子量が50kDa〜100kDaである、請求項1又は2に記載の増殖抑制剤。
- 分散化メラニンの平均粒子径が70nm〜130nmである、請求項1に記載の増殖抑制剤。
- 細胞が腫瘍細胞である、請求項1〜4のいずれか一項に記載の増殖抑制剤。
- がんの治療に使用される、請求項5に記載の増殖抑制剤。
- 抗がん剤が併用される、請求項6に記載の増殖抑制剤。
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