JP2018536706A - がんの治療のためのカンナビジオール及び第二の治療剤を含む組成物 - Google Patents
がんの治療のためのカンナビジオール及び第二の治療剤を含む組成物 Download PDFInfo
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Abstract
【選択図】なし
Description
本発明は、がんの治療において効果的である、カンナビジオールと、第二の治療剤との組合せに関する。第二の治療剤としては、1以上のChEH/AEBS阻害剤、ナフトキノン若しくはその誘導体、又はそれらの組合せが挙げられる。
***の主要な非精神活性成分である、カンナビジオール (CBD)は、腫瘍細胞に対する、そのin vitro及びin vivo活性に基づいて抗新生物剤と考えられる。向精神薬活性が無いために、その薬理学及び治療上の可能性が集中的に研究されている。最近の研究によって、CBDは免疫抑制性、抗炎症性、抗けいれん性、抗不安性、抗精神病性、神経保護性及び抗悪心性の効果を含む、様々な興味深い薬理作用を有することが、実証されている。その治療における可能性は、多発性硬化症に関連する神経障害性疼痛を緩和するための、およそ等量のΔ9-テトラヒドロカンナビノール (THC)及びCBDを含む、カンナビノイドベースの医薬の、カナダにおける最近の承認によって更に立証されている。
一実施形態においては、本発明は、例えば、血液のがん、骨髄関連のがん、乳がん及び膠芽細胞腫等であるが、それに限定されない悪性腫瘍の治療において効果がある、カンナビジオール (CBD)と少なくとも1つのChEH/AEBS阻害剤とを含む組成物である。
試薬:試薬は販売会社から購入し、100% DMSO(DMSOand)に溶解し、-20℃で保存した。DMSOの終濃度は0.1%であった。アクリジンオレンジ/エチジウムブロマイド染色剤は、PBS中において1 mg/mlの濃度で調製した。XTT及び他の全ての化学物質はSigma (St. Louis, MO)から入手した。対照培養は、それ自体は効果がないビヒクルを含んだ。
カンナビジオールとChEH/AEBS阻害剤との組合せによってがん細胞生存率における低減が起こる
HL-60、CCRF-CEM、A-172及びMCF-7細胞株の生存率に対する、カンナビジオールとChEH/AEBS阻害剤との組合せを曝露した影響を、in vitroで調べた。この目的を達成するために、腫瘍細胞を10%FCS補充培地中で培養し、5%FCS含有培地並びに1、5、10及び30μMのChEH/AEBS阻害剤中で、様々な濃度のカンナビジオール (1、5、10及び30μM)に、48時間曝露した(図1、2、3及び4)。
カンナビジオール、TPE (クロミフェン及びタモキシフェン)並びにメナジオンは、細胞生存率における減少を引き起こす
HL-60及びCCRF-CEM、A-172及びMCF-7細胞株の生存率に対する、カンナビジオール曝露の影響を、in vitroで調べた。この目的を達成するために、腫瘍細胞を10%FCS補充培地中で培養し、10%又は5%FCS含有培地中において様々な濃度のカンナビジオール (5、10、15、20及び30μM)に24時間及び48時間曝露し、血清フリー培地中において、0.01、0.03、0.1、0.3、1、3及び5μM CBDに24時間曝露した (図9A、9B、9C及び9D)。結果は、5μM以上の濃度でカンナビジオールに24時間及び48時間処理に曝露すると、生存細胞数において有意な減少が起こることを示す (図9A、9B、9C及び9D)。細胞生存率における減少は、24及び48時間曝露の両方で用量応答性であった (図9A、9B、9C及び9D)。CBDは、血清フリー条件下で、たとえ非常に低い濃度(0.2μM)であっても、24時間の曝露で、細胞生存率の減少に対する強力な効果を有した。48時間後、10%FCS培地中で得られたIC50値は16μMであった。培地中での血清濃度を下げて (5%FCS)、24時間におけるIC50もまた求めた。血清フリー培地中で、IC50は24時間で0.26μMであった。10%FCS培地中で、細胞は、24時間で、CBDに対してより感受性が低いことが判明した。細胞生存率の減少の統計的有意性はP<0.05であった。
CBDと、TPE及びナフトキノンとの相乗効果
本研究において、CBDはクロミフェン、タモキシフェン及びメナジオンと相乗的な抗がん効果を有していた(図12 A、B、C)。図4に示すように、CBDと、クロミフェン、タモキシフェン及びメナジオンとの組合せ(combination CBD, clomiphene, tamoxifen and menadione)は、HL-60細胞の生存率を効果的に低減した。最も効果的な組合せは、5μM CBDと15μM クロミフェン (図12A)、10μM CBDと10μM タモキシフェン (図12B)であることが見出された。メナジオンとCBDは、高濃度のメナジオンで細胞生存率を低減することにおいて相加するものを超える(more than additive)ことを示した (図12C)。従来の化学療法薬アントラサイクリン、ドキソルビシンは、HL-60細胞の生存率における低減において、CBDとの相加効果を示した(図13)。
核の形態変化はアポトーシスの特徴である
がん細胞株のアポトーシスに対するCBDの影響を調べた。CBDは、HL-60及びCCRF-CEM細胞株の両方において、用量及び時間依存的なアポトーシスの誘導を示した(図17A及び図18A)。CBDとTPEとの組合せはアポトーシスの誘導において相乗効果があった一方で、メナジオンとの組合せでは、CBDはHL-60細胞株のアポトーシスの誘導において相加効果より高い効果を示した(図17B及び17C)。同様の結果がまたCCRF-CEM細胞株で見られた(図18)。代表的な顕微鏡写真を図19に示す。
CBDを用いたMcl-1の下方制御
Mcl-1の過剰発現は、白血病細胞の生存と関連する;CBDはCCRF-CEM細胞中のMcl-1発現を下方制御した。CBDは、3時間の処理によって、Mcl-1の下方制御を示した(図20)。
HL-60細胞を移植したマウス異種移植モデルにおける腫瘍増殖の阻害
異種移植したマウスを5 mg/kg CBD、10 mg/kg CL単独、及び組合せで処理したことによって、7〜14日目でHL-60腫瘍増殖の有意な抑制がもたらされた(図21)。
AML及びCLL初代細胞に対するCBD及びクロミフェンの効果
AML及びCLL初代細胞に対するCBD及びクロミフェンの細胞毒性効果についても評価した。5μMクロミフェンと10μM CBDは相乗的に、24時間以内に細胞死を誘導した(図22)。
Claims (55)
- カンナビジオール (CBD)と、少なくとも1つのChEH/AEBS阻害剤化合物との相乗的な組合せを含む組成物であって、ChEH/AEBS阻害剤化合物がSERMではない、組成物。
- 前記ChEH/AEBS阻害剤化合物がChEH/AEBSの選択的阻害剤である、請求項1に記載の組成物。
- 前記ChEH/AEBSの選択的阻害剤がPBPE又はテスミリフェン (DPPE)である、請求項2に記載の組成物。
- 前記ChEH/AEBS阻害剤化合物がDPPEである、請求項3に記載の組成物。
- 前記ChEH/AEBS阻害剤がコレステロール生合成阻害剤である、請求項1に記載の組成物。
- 前記コレステロール生合成阻害剤がトリパラノール、テルビナフィン若しくはU-18666A、又はそれらの組合せである、請求項5に記載の組成物。
- 前記コレステロール生合成阻害剤がトリパラノールである、請求項6に記載の組成物。
- 前記ChEH/AEBS阻害剤化合物がB環オキシステロールである、請求項1に記載の組成物。
- 前記B環オキシステロールが6-ケトコレスタノール、7-ケトコレスタノール、7-ケトコレステロール及びコレスタン-3b,5a,6b-トリオール(CT)、又はそれらの組合せである、請求項8に記載の組成物。
- 前記B環オキシステロールがコレスタン-3b,5a,6b-トリオール(CT)である、請求項9に記載の組成物。
- 前記ChEH/AEBS阻害剤化合物が不飽和脂肪酸である、請求項1に記載の組成物。
- 前記不飽和脂肪酸がオレイン酸、アラキドン酸 (ARA)若しくはドコサヘキサエン酸 (DHA)、又はそれらの組合せである、請求項11に記載の組成物。
- 医薬的に許容される担体を更に含む、請求項1に記載の組成物。
- がんの治療における使用のための、請求項1〜13のいずれか一項に記載の組成物。
- がんの治療をする方法であって、それを必要とする対象に、治療有効量の請求項1〜13のいずれか一項に記載の組成物を投与することを含む、方法。
- がんの治療をする方法であって、それを必要とする対象に、治療有効量のカンナビジオール (CBD)とChEH/AEBS阻害剤との相乗的な組合せを投与することを含み、ChEH/AEBS阻害剤化合物がSERMではない、方法。
- 前記がんが、胆管のがん、膀胱のがん、骨のがん、腸のがん (結腸のがん及び直腸のがんを含む)、脳のがん、胸のがん、神経内分泌系のがん (一般的にカルチノイドとして知られる)、子宮頸部のがん、目のがん、食道のがん、頭部及び頸部のがん (このグループとしては、口、鼻、喉、耳、又は舌を覆う表層、の裏地を形成する細胞において始まる上皮性悪性腫瘍が挙げられる)、カポジ肉腫、腎臓のがん、喉頭のがん、白血病:急性白血病、慢性リンパ性白血病、肝臓のがん、肺のがん、リンパ節のがん、ホジキンリンパ腫、非ホジキンリンパ腫、黒色腫、中皮腫、骨髄腫、 卵巣のがん、膵臓のがん、陰茎のがん、前立腺のがん、皮膚がん、軟部組織肉腫、脊髄のがん、胃のがん、精巣がん、甲状腺のがん、膣のがん、外陰部のがん及び子宮のがんである、請求項15〜16のいずれか一項に記載の方法。
- 血液又は骨髄関連がんを患っている対象の治療を、それを必要とする対象においてする方法であって、治療有効量のカンナビジオール (CBD)とChEH/AEBS阻害剤との相乗的な組合せを前記対象に投与することを含み、ChEH/AEBS阻害剤化合物がSERMではない、方法。
- 血液又は骨髄関連がんを患っている対象の治療を、それを必要とする対象においてする方法であって、治療有効量の請求項1〜13のいずれか一項に記載の組成物を前記対象に投与することを含む、方法。
- 膠芽細胞腫を患っている対象の治療を、それを必要とする対象においてする方法あって、治療有効量のカンナビジオール (CBD)とChEH/AEBS阻害剤との相乗的な組合せを前記対象に投与することを含み、ChEH/AEBS阻害剤化合物がSERMではない、方法。
- 膠芽細胞腫を患っている対象の治療を、それを必要とする対象においてする方法であって、治療有効量の請求項1〜13のいずれか一項に記載の組成物を前記対象に投与することを含む、方法。
- 乳がんを患っている対象の治療を、それを必要とする対象においてする方法であって、治療有効量のカンナビジオール (CBD)とChEH/AEBS阻害剤との相乗的な組合せを前記対象に投与することを含み、ChEH/AEBS阻害剤化合物がSERMではない、方法。
- 乳がんを患っている対象の治療を、それを必要とする対象においてする方法であって、治療有効量の請求項1〜13のいずれか一項に記載の組成物を前記対象に投与することを含む、方法。
- エストロゲン受容体陰性がんの治療における使用のための、カンナビジオール (CBD)と、少なくとも1つのChEH/AEBS阻害剤化合物との相乗的な組合せを含む、組成物。
- 前記ChEH/AEBS阻害剤化合物がChEH/AEBSの選択的阻害剤である、請求項24に記載の組成物。
- 前記ChEH/AEBSの選択的阻害剤がPBPE又はテスミリフェン (DPPE)である、請求項24に記載の組成物。
- 前記ChEH/AEBS阻害剤化合物がDPPEである、請求項26に記載の組成物。
- 前記ChEH/AEBS阻害剤がコレステロール生合成阻害剤である、請求項4に記載の組成物。
- 前記コレステロール生合成阻害剤がトリパラノール、テルビナフィン若しくはU-18666A、又はそれらの組合せである、請求項26に記載の組成物。
- 前記コレステロール生合成阻害剤がトリパラノールである、請求項27に記載の組成物。
- 前記ChEH/AEBS阻害剤化合物がB環オキシステロールである、請求項24に記載の組成物。
- 前記B環オキシステロールが6-ケトコレスタノール、7-ケトコレスタノール、7-ケトコレステロール及びコレスタン-3b,5a,6b-トリオール(CT)、又はそれらの組合せである、請求項29に記載の組成物。
- 前記B環オキシステロールがコレスタン-3b,5a,6b-トリオール(CT)である、請求項30に記載の組成物。
- 前記ChEH/AEBS阻害剤化合物が不飽和脂肪酸である、請求項24に記載の組成物。
- 前記不飽和脂肪酸がオレイン酸、アラキドン酸 (ARA)若しくはドコサヘキサエン酸 (DHA)、又はそれらの組合せである、請求項32に記載の組成物。
- 医薬的に許容される担体を更に含む、請求項24に記載の組成物。
- 前記ChEH/AEBS阻害剤化合物が、カチオン性アミノエトキシ側鎖を含む選択的エストロゲン受容体モジュレーター (SERM)である、請求項24に記載の組成物。
- 前記SERMがクロミフェン、タモキシフェン、4-ヒドロキシ-タモキシフェン、ラロキシフェン、又はそれらの組合せである、請求項37に記載の組成物。
- 前記SERMがトリフェニルエチレン (TPE)若しくはカチオン性アミノエトキシ側鎖を含むその誘導体、又はその組合せである、請求項37に記載の組成物。
- エストロゲン受容体陰性がんの治療をする方法であって、それを必要とする対象に、治療有効量の請求項24〜39のいずれか一項に記載の組成物を投与することを含む、方法。
- エストロゲン受容体陰性がんの治療をする方法であって、それを必要とする対象に、治療有効量のカンナビジオール (CBD)とChEH/AEBS阻害剤との相乗的な組合せを投与することを含む、方法。
- 前記がんが、胆管のがん、膀胱のがん、骨のがん、腸のがん、脳のがん、胸のがん、神経内分泌系のがん、子宮頸部のがん、目のがん、食道のがん、頭部及び頸部のがん、カポジ肉腫、腎臓のがん、喉頭のがん、白血病:急性白血病、慢性リンパ性白血病、肝臓のがん、肺のがん、リンパ節のがん、ホジキンリンパ腫、非ホジキンリンパ腫、黒色腫、中皮腫、骨髄腫、卵巣のがん、膵臓のがん、陰茎のがん、前立腺のがん、皮膚がん、軟部組織肉腫、脊髄のがん、胃のがん、精巣がん、甲状腺のがん、膣のがん、外陰部のがん及び子宮のがんである、請求項40〜41のいずれか一項に記載の方法。
- カンナビジオール (CBD)と、少なくとも1つのナフトキノン又はその誘導体との相乗的な組合せを含む、組成物。
- 前記ナフトキノン又はその誘導体がメナジオンである、請求項43に記載の組成物。
- 医薬的に許容される担体を更に含む、請求項43に記載の組成物。
- がんの治療における使用のための、請求項43〜45のいずれか一項に記載の組成物。
- がんの治療をする方法であって、それを必要とする対象に、治療有効量の請求項43〜45のいずれか一項に記載の組成物を投与することを含む、方法。
- がんの治療をする方法であって、それを必要とする対象に、治療有効量のカンナビジオール (CBD)と、ナフトキノン又はその誘導体との相乗的な組合せを投与することを含む、方法。
- 前記がんが、胆管のがん、膀胱のがん、骨のがん、腸のがん、脳のがん、胸のがん、神経内分泌系のがん、子宮頸部のがん、目のがん、食道のがん、頭部及び頸部のがん、カポジ肉腫、腎臓のがん、喉頭のがん、白血病:急性白血病、慢性リンパ性白血病、肝臓のがん、肺のがん、リンパ節のがん、ホジキンリンパ腫、非ホジキンリンパ腫、黒色腫、中皮腫、骨髄腫、卵巣のがん、膵臓のがん、陰茎のがん、前立腺のがん、皮膚がん、軟部組織肉腫、脊髄のがん、胃のがん、精巣がん、甲状腺のがん、膣のがん、外陰部のがん及び子宮のがんである、請求項47〜48のいずれか一項に記載の方法。
- 血液又は骨髄関連がんを患っている対象の治療を、それを必要とする対象においてする方法であって、治療有効量のカンナビジオール (CBD)と、ナフトキノン又はその誘導体との相乗的な組合せを、前記対象に投与することを含む、方法。
- 血液又は骨髄関連がんを患っている対象の治療を、それを必要とする対象においてする方法であって、治療有効量の請求項43〜45のいずれか一項に記載の組成物を、前記対象に投与することを含む、方法。
- 膠芽細胞腫を患っている対象の治療を、それを必要とする対象においてする方法であって、治療有効量のカンナビジオール (CBD)と、ナフトキノン又はその誘導体との相乗的な組合せを、前記対象に投与することを含む、方法。
- 膠芽細胞腫を患っている対象の治療を、それを必要とする対象においてする方法であって、治療有効量の請求項43〜45のいずれか一項に記載の組成物を、前記対象に投与することを含む、方法。
- 乳がんを患っている対象の治療を、それを必要とする対象においてする方法であって、治療有効量のカンナビジオール (CBD)と、ナフトキノン又はその誘導体との相乗的な組合せを、前記対象に投与することを含む、方法。
- 乳がんを患っている対象の治療を、それを必要とする対象においてする方法であって、治療有効量の請求項43〜45のいずれか一項に記載の組成物を、前記対象に投与することを含む、方法。
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US20230157987A1 (en) * | 2020-04-09 | 2023-05-25 | Steven Robert LAVIOLETTE | Combination of cannabidiol and a ppar agonist |
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WO2023076928A1 (en) | 2021-10-26 | 2023-05-04 | Ecofibre Limited | Methods of treating ovarian cancer with hemp extract |
AU2022379618A1 (en) | 2021-10-26 | 2024-05-23 | Ecofibre USA Inc. | Methods of treating endometriosis and other non-cancer gynecological disorders with hemp extract |
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