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Can Necroptosis Promote Myeloma?
Can necroptosis promote myeloma? At first glance this question makes no sense because necroptosis is a form of cell death caused by chemotherapy.
The problem comes with the second article linked below that talks about researchers at Moffitt Ctr. documenting the release of necropolis “can actually make tumors grow faster by turning off the immune system’s ability to fight the cancer.”
Here’s what ChatGPT has to say on the issue of necroptosis and MM regimens.
Which chemotherapy regimens used for multiple myeloma cause necroptosis?
“Necroptosis, a form of programmed cell death distinct from apoptosis, involves receptor-interacting protein kinases (RIPK1 and RIPK3) and mixed-lineage kinase domain-like pseudokinase (MLKL). In multiple myeloma (MM), certain chemotherapy agents may induce necroptosis as part of their anti-cancer effects.
Chemotherapy Regimens and Drugs Linked to Necroptosis in Multiple Myeloma
While specific regimens targeting necroptosis in MM are not widely established, several drugs used in MM treatment have been associated with necroptotic pathways in preclinical studies:
- Bortezomib (Proteasome Inhibitor)
- Bortezomib induces cellular stress, leading to the accumulation of misfolded proteins. This can activate necroptosis, particularly when apoptosis is impaired, as observed in some MM cell lines. It may involve the RIPK1-RIPK3-MLKL pathway.
- Lenalidomide and Pomalidomide (Immunomodulatory Drugs, IMiDs)
- While these agents primarily enhance immune-mediated cytotoxicity and induce apoptosis, some studies suggest they can trigger necroptosis under certain conditions, such as when combined with other stress-inducing agents.
- Dexamethasone (Corticosteroid)
- Typically used for its anti-inflammatory and anti-myeloma effects, dexamethasone can modulate necroptosis pathways, particularly in combination with proteasome inhibitors.
- Melphalan (Alkylating Agent)
- Melphalan causes DNA damage, which may indirectly lead to necroptosis if apoptosis pathways are defective.
- Combination Therapies
- Regimens such as VRd (Bortezomib, Lenalidomide, Dexamethasone) or CyBorD (Cyclophosphamide, Bortezomib, Dexamethasone) might induce necroptosis, especially in resistant MM cells.
I’m a long-term myeloma survivor not an oncologist. Most of the content linked below was impossible for me to understand. However, my layman’s mind understands:
- MM always relapses
- MM is susceptible to necroptosis
- Most all MM patients undergo one or more of the regimens listed above that cause necroptosis
While I certainly am NOT suggesting that MM patients avoid protease inhibitors, immunomodulatory drugs, melphalan and dexamethasone, I am suggesting that mm patients consider taking a low-dose approach to managing their myeloma.
Email me at David.PeopleBeatingCancer@gmail.com with questions about MM.
Thank you,
David Emerson
- MM Survivor
- MM Cancer Coach
- Director PeopleBeatingCancer
Cell Death Triggers Induce MLKL Cleavage in Multiple Myeloma Cells, Which may Promote Cell Death
Necroptosis is a type of caspase-independent programmed cell death that has been implicated in cancer development…
Here, we demonstrate that omega-3 polyunsaturated fatty acids DHA/EPA and the proteasome inhibitor bortezomib induce necroptosis in human multiple myeloma (MM) cells in a RIPK3 independent manner…
We show that treatment of MM cells with these cytotoxic compounds induced cleavage of MLKL into a 35 kDa protein…
Discussion
In the present study, we show that cell death triggers such as DHA, EPA and bortezomib may induce necroptosis in multiple myeloma cells independent of RIPK3…
Caspases-3/8/10 Cleave MLKL in MM Cells
We further addressed how MLKL is cleaved after treatment of MM cells with cytotoxic agents. Caspases are best-known intracellular proteases that hydrolyze a broad range of protein substrates by recognizing specific cleavage motifs in their sequences…
Results
Necroptosis Is Involved in DHA/EPA and Bortezomib-Induced Cell Death in MM Cells
Given the crucial role of necroptosis in the development of many types of human cancers (23), involvement of the necroptotic pathway was further investigated in bortezomib and DHA/EPA-induced cell death in MM cells…
In addition, bortezomib caused a potent decrease of MLKL in all MM cell lines in a concentration- and time-dependent manner, as shown in Figures 2C, D …
MLKL Is Indeed Cleaved by the Induction of Bortezomib in MM Cells
To directly validate the potential cleavage of MLKL, endogenous MLKL was pulled down from DMSO or bortezomib-treated OPM2 and L363 cells using an anti-C-terminal MLKL antibody…
Discussion
In the present study, we show that cell death triggers such as DHA, EPA and bortezomib may induce necroptosis in multiple myeloma cells independent of RIPK3…
Conclusion
Necroptosis has been implicated in a wide range of human diseases. A better understanding of the underlying regulatory mechanisms would help development of new therapeutics for necroptosis-associated human diseases…
Taken together, the present study suggests a novel role and regulatory mechanisms of necroptosis in multiple myeloma, and may provide a new molecular target (avenue) for therapeutic intervention of certain human cancers with eliminated RIPK3 function.”
Study links cell death pathway to cancer resistance and growth
“A new study has uncovered an unexpected way cancer cells can escape the immune system, making it harder for treatments to work. The study, published in Cancer Cell, explains how a type of cancer cell death can actually make tumors grow faster by turning off the immune system’s ability to fight the cancer.
Researchers at Moffitt Cancer Center focused on a form of cell death called necroptosis. Previously thought to help the immune system fight cancer, researchers found that when cancer cells die in this way, they can release a molecule called interleukin-1α. This molecule helps create an environment in the tumor that weakens the immune response, preventing T cells from attacking the cancer.
“We thought necroptosis would help the immune system fight cancer, but instead, it seems to make things worse by helping tumors grow…”
The study also found that interleukin-1α is released by cancer cells responding to chemotherapy, which could explain why some treatments don’t work as well as expected…
Interleukin-1α release during necrotic-like cell death generates myeloid-driven immunosuppression that restricts anti-tumor immunity
“Highlights
- Induced necroptosis promotes immune suppression and tumor growth
- Necroptosis-mediated immune suppression occurs through release of IL-1α
- IL-1α reprograms the myeloid microenvironment and limits anti-tumor immunity
- Neutralizing IL-1α enhances the immune-dependent response to chemotherapy..”
necroptosis promote myeloma? necroptosis promote myeloma?