The combination of GZ17-6.02 with proteasome inhibitors effectively targets and eliminates multiple myeloma cells.
A groundbreaking study published in Oncotarget's Volume 15 on March 5, 2024, titled "GZ17-6.02 interacts with proteasome inhibitors to kill multiple myeloma cells," sheds light on a promising new approach for combating multiple myeloma, a type of cancer that affects plasma cells in the bone marrow. The research, led by Laurence Booth, Jane L. Roberts, Cameron West, and Paul Dent from Virginia Commonwealth University and Genzada Pharmaceuticals, delves into the effectiveness of GZ17-6.02, a compound comprising isovanillin, harmine, and curcumin, in targeting multiple myeloma cells.
GZ17-6.02 has already shown promise in phase I trials for solid tumors, with a recommended phase 2 dose of 375 mg PO BID. What sets GZ17-6.02 apart is its superior efficacy in killing multiple myeloma cells compared to its performance in solid tumor cell types. The study highlights that the compound interacts synergistically with proteasome inhibitors, particularly bortezomib, to effectively eliminate myeloma cells. Even in cases where cells were resistant to inhibitors, GZ17-6.02 was able to induce cell death to a significant degree.
The combination of GZ17-6.02 and bortezomib triggers a cascade of molecular events within the cells. This includes the activation of key signaling pathways such as ATM, AMPK, and PERK, while simultaneously inhibiting ULK1, mTORC1, eIF2α, NFκB, and the Hippo pathway. The treatment regimen also upregulates the expression of crucial proteins involved in autophagy, such as Beclin1, ATG5, BAK, and BIM, while downregulating anti-apoptotic proteins like BCL-XL and MCL1. Notably, the combination therapy promotes autophagosome formation and enhances autophagic flux, crucial processes for degrading and recycling cellular components. Knockdown experiments further highlighted the importance of various proteins in mediating the cytotoxic effects of the treatment, with inhibition of ATM, AMPKα, ULK1, Beclin1, or ATG5 significantly reducing both autophagy and cell death. Knockdown of BAK and BIM also demonstrated a reduction in tumor cell killing, underscoring their role in the process.
Furthermore, the study revealed a significant reduction in the expression of histone deacetylases (HDACs) 1, 2, and 3, beyond levels observed in solid tumor cells. This reduction was found to be dependent on autophagy and was associated with increased acetylation and methylation of histone H3. Simultaneous knockdown of HDACs 1, 2, and 3 led to the activation of ATM and AMPK signaling pathways, as well as the inhibition of ULK1, mTORC1, NFκB, and the Hippo pathway. The combined knockdown also increased ATG13 phosphorylation, elevated BAK protein levels, and reduced the levels of the anti-apoptotic protein BCL-XL.
The researchers emphasize the need for further in vivo studies to validate the efficacy of GZ17-6.02 in combating multiple myeloma. The study's findings open up new avenues for developing therapeutic strategies that could potentially prolong the survival of patients with this challenging disease.
In conclusion, the study underscores the potential of GZ17-6.02 in combination with proteasome inhibitors as a promising therapeutic approach for multiple myeloma. By elucidating the molecular mechanisms underlying the compound's efficacy, the research paves the way for future investigations and clinical trials aimed at harnessing the full potential of this novel treatment strategy.
Source: https://www.eurekalert.org/news-releases/1036817
GZ17-6.02 has already shown promise in phase I trials for solid tumors, with a recommended phase 2 dose of 375 mg PO BID. What sets GZ17-6.02 apart is its superior efficacy in killing multiple myeloma cells compared to its performance in solid tumor cell types. The study highlights that the compound interacts synergistically with proteasome inhibitors, particularly bortezomib, to effectively eliminate myeloma cells. Even in cases where cells were resistant to inhibitors, GZ17-6.02 was able to induce cell death to a significant degree.
The combination of GZ17-6.02 and bortezomib triggers a cascade of molecular events within the cells. This includes the activation of key signaling pathways such as ATM, AMPK, and PERK, while simultaneously inhibiting ULK1, mTORC1, eIF2α, NFκB, and the Hippo pathway. The treatment regimen also upregulates the expression of crucial proteins involved in autophagy, such as Beclin1, ATG5, BAK, and BIM, while downregulating anti-apoptotic proteins like BCL-XL and MCL1. Notably, the combination therapy promotes autophagosome formation and enhances autophagic flux, crucial processes for degrading and recycling cellular components. Knockdown experiments further highlighted the importance of various proteins in mediating the cytotoxic effects of the treatment, with inhibition of ATM, AMPKα, ULK1, Beclin1, or ATG5 significantly reducing both autophagy and cell death. Knockdown of BAK and BIM also demonstrated a reduction in tumor cell killing, underscoring their role in the process.
Furthermore, the study revealed a significant reduction in the expression of histone deacetylases (HDACs) 1, 2, and 3, beyond levels observed in solid tumor cells. This reduction was found to be dependent on autophagy and was associated with increased acetylation and methylation of histone H3. Simultaneous knockdown of HDACs 1, 2, and 3 led to the activation of ATM and AMPK signaling pathways, as well as the inhibition of ULK1, mTORC1, NFκB, and the Hippo pathway. The combined knockdown also increased ATG13 phosphorylation, elevated BAK protein levels, and reduced the levels of the anti-apoptotic protein BCL-XL.
The researchers emphasize the need for further in vivo studies to validate the efficacy of GZ17-6.02 in combating multiple myeloma. The study's findings open up new avenues for developing therapeutic strategies that could potentially prolong the survival of patients with this challenging disease.
In conclusion, the study underscores the potential of GZ17-6.02 in combination with proteasome inhibitors as a promising therapeutic approach for multiple myeloma. By elucidating the molecular mechanisms underlying the compound's efficacy, the research paves the way for future investigations and clinical trials aimed at harnessing the full potential of this novel treatment strategy.
Source: https://www.eurekalert.org/news-releases/1036817
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