ビタミンCは,GAPDHを標的として,KRASとBRAF変異性大腸がん細胞を選択的に殺します
Jihye Yun1, Edouard Mullarky2, Changyuan Lu3
1Meyer Cancer Center, Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
まとめ
高用量ビタミンCは,酸化ストレスとエネルギー危機を誘発することによって,KRASまたはBRAF変異を有する大腸がん細胞を選択的に殺します. この発見は 治療が難しいがんの 新しい治療法となる可能性があります
科学分野:
- 腫瘍学
- 生物化学
- 分子生物学
背景:
- 結腸直腸がん (CRC) はしばしばKRASまたはBRAF変異を宿し,標的治療に対する耐性を引き起こす.
- KRAS/BRAF変異性CRCに対する効果的な治療戦略は,依然として限られている.
研究 の 目的:
- KRASまたはBRAF変異性大腸がん細胞に対する高用量ビタミンCの選択的抗癌効果を調査する.
- これらの特定の癌の細胞死の原因となる分子メカニズムを解明する.
主な方法:
- KRASまたはBRAF変異と野生型の同位体を持つ培養されたヒトCRC細胞を使用した.
- 高用量ビタミンC (デヒドロアスコルベート,DHA) のGLUT1による摂取の影響を評価した.
- 酸化ストレス,グルタチオン濃度,およびグリセラルデヒド3酸塩脱水素酶 (GAPDH) の活性が測定されました.
- Apc/Kras (G12D) ミュータントマウスモデルでの腫瘍の成長評価
主要な成果:
- 高レベルのビタミンCは,培養KRASまたはBRAF変異CRC細胞で選択的に細胞死を誘発する.
- この効果は,GLUT1によるDHAの吸収の増加によって引き起こされ,酸化ストレスとグルタチオンの枯渇を引き起こします.
- 蓄積された反応性酸素種はGAPDHを無効化し,変異細胞のエネルギー危機を引き起こします.
- 高用量ビタミンCはマウスモデルで腫瘍の成長を抑制することが示された.
結論:
- 高用量ビタミンCは,KRAS/ BRAF変異性大腸がんに対して選択的細胞毒性を示す.
- このメカニズムはDHA誘発の酸化ストレス,GAPDH阻害,そしてその後の代謝崩壊を含みます.
- ビタミンCは,KRASとBRAF変異性CRCに対する有望な治療法です.
さらに関連する動画
10:13A Multiplexed Luciferase-based Screening Platform for Interrogating Cancer-associated Signal Transduction in Cultured Cells
Published on: July 3, 2013
11.8K
07:49Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
Published on: July 17, 2019
6.6K
関連する概念動画
The Ras Gene
7.5K
The Ras-gene-encoded proteins are regulators of signaling pathways controlling cell proliferation, differentiation, or cell survival. The Ras-gene family in humans constitutes three primary members—the HRas, NRas, and KRas. These genes code for four functionally distinct yet closely related proteins—the HRas, NRas, KRas4A, and KRas4B. The involvement of mutant Ras genes in human cancer was first discovered in 1982 and is among the most common causes of human tumorigenesis.
Ras is a...
Ras is a...
7.5K
Targeted Cancer Therapies
9.1K
The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
There are several types of targeted therapies against...
There are several types of targeted therapies against...
9.1K
Targeted Cancer Therapies
1.8K
1.8K
Inhibition of Cdk Activity
6.2K
The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
6.2K
Small GTPases - Ras and Rho
5.7K
Ras and Rho are small monomeric GTPases that act downstream of receptor tyrosine kinase (RTK) and regulate various cellular processes. These GTPases switch between active and inactive states by binding to guanine nucleotides.
Three regulatory proteins control their activity:
Three regulatory proteins control their activity:
5.7K
Combination Therapies and Personalized Medicine
6.3K
Combining two or more treatment methods increases the life span of cancer patients while reducing damage to vital organs or tissue from the overuse of a single treatment. Combination therapy also targets different cancer-inducing pathways, thus reducing the chances of developing resistance to treatment.
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...
6.3K
