{"id":{"repo_id":"plymouth","oai_identifier":"oai:pearl.plymouth.ac.uk:bhs-theses-1021"},"canonical_url":"https://search.dev.ndltd.org/etd/plymouth/oai:pearl.plymouth.ac.uk:bhs-theses-1021","repository":{"repo_id":"plymouth","name":"University of Plymouth","base_url":"https://pearl.plymouth.ac.uk/do/oai"},"display":{"title":"Investigating the metabolic impact of Metformin and Berberine in combination with Venetoclax for Acute Myeloid Leukaemia treatment","abstract":"Acute myeloid leukaemia (AML) stands as a significant challenge in haematological malignancies, particularly due to poor outcomes in older patients and resistance to therapy. BCL-2, an anti-apoptotic protein, is overexpressed in AML. The BCL-2 antagonist Venetoclax inhibits OXPHOS and induces apoptosis in AML cells, which is potentiated when combined with Metformin an anti-hyperglycaemic agent used to treat type 2 diabetes, which also has anti-cancer properties. This study explored the effects of Venetoclax combined with Metformin or Berberine, an herbal supplement with a similar mechanism of action to metformin, on AML cell death and metabolic changes. The combination of Metformin and Venetoclax (Met+Ven) showed a synergistic cell death response in the HL60 cell line, unlike Berberine and Venetoclax (BBR+Ven). The combination treatments increased lactate production compared to their monotherapy, however Met+Ven increased lactate retention and reduced expression of the lactate efflux protein MCT4, whereas BBR+Ven increased MCT4 expression. Both combinations increased mitochondrial membrane permeability, correlating with increased cell death. Proteomic analysis of Met+Ven treated cells revealed decreased expression of core mitochondrial respiratory chain complex 1 protein (NDUFV1) and alterations in complex 4 proteins (increased COX5A, decreased NDUFA4). Additionally, endoplasmic reticulum proteins related to protein folding and ubiquitylation were upregulated, suggesting endoplasmic reticulum stress. These findings suggest that the Met+Ven combination could induce both ER and mitochondrial stress, leading to increased calcium flux and necroptosis, and could have clinical applications to patients who are ineligible for induction chemotherapy.","abstract_html":"Acute myeloid leukaemia (AML) stands as a significant challenge in haematological malignancies, particularly due to poor outcomes in older patients and resistance to therapy. BCL-2, an anti-apoptotic protein, is overexpressed in AML. The BCL-2 antagonist Venetoclax inhibits OXPHOS and induces apoptosis in AML cells, which is potentiated when combined with Metformin an anti-hyperglycaemic agent used to treat type 2 diabetes, which also has anti-cancer properties. This study explored the effects of Venetoclax combined with Metformin or Berberine, an herbal supplement with a similar mechanism of action to metformin, on AML cell death and metabolic changes. The combination of Metformin and Venetoclax (Met+Ven) showed a synergistic cell death response in the HL60 cell line, unlike Berberine and Venetoclax (BBR+Ven). The combination treatments increased lactate production compared to their monotherapy, however Met+Ven increased lactate retention and reduced expression of the lactate efflux protein MCT4, whereas BBR+Ven increased MCT4 expression. Both combinations increased mitochondrial membrane permeability, correlating with increased cell death. Proteomic analysis of Met+Ven treated cells revealed decreased expression of core mitochondrial respiratory chain complex 1 protein (NDUFV1) and alterations in complex 4 proteins (increased COX5A, decreased NDUFA4). Additionally, endoplasmic reticulum proteins related to protein folding and ubiquitylation were upregulated, suggesting endoplasmic reticulum stress. These findings suggest that the Met+Ven combination could induce both ER and mitochondrial stress, leading to increased calcium flux and necroptosis, and could have clinical applications to patients who are ineligible for induction chemotherapy.","abstract_has_math":false,"creators":["Robins, Samantha"],"institution":null,"degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":["Kris Jeremy, Vikram Sharma, Andrew Foey, Shagun Khera"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2025,"date_issued":"2025-01-01T08:00:00Z","date_published":"2025-01-01T08:00:00Z","updated_at":"2026-07-24T03:49:35Z","subjects":[],"languages":["eng"],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://pearl.plymouth.ac.uk/bhs-theses/22","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Kris Jeremy, Vikram Sharma, Andrew Foey, Shagun Khera"]},{"key":"dc:creator","label":"Author","values":["Robins, Samantha"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.available","label":"Dc Date Available","values":["2025-02-26T08:00:00Z"]},{"key":"dc:date.issued","label":"Date","values":["2025-01-01T08:00:00Z"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["eng"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://pearl.plymouth.ac.uk/bhs-theses/22"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Acute myeloid leukaemia (AML) stands as a significant challenge in haematological malignancies, particularly due to poor outcomes in older patients and resistance to therapy. BCL-2, an anti-apoptotic protein, is overexpressed in AML. The BCL-2 antagonist Venetoclax inhibits OXPHOS and induces apoptosis in AML cells, which is potentiated when combined with Metformin an anti-hyperglycaemic agent used to treat type 2 diabetes, which also has anti-cancer properties. This study explored the effects of Venetoclax combined with Metformin or Berberine, an herbal supplement with a similar mechanism of action to metformin, on AML cell death and metabolic changes. The combination of Metformin and Venetoclax (Met+Ven) showed a synergistic cell death response in the HL60 cell line, unlike Berberine and Venetoclax (BBR+Ven). The combination treatments increased lactate production compared to their monotherapy, however Met+Ven increased lactate retention and reduced expression of the lactate efflux protein MCT4, whereas BBR+Ven increased MCT4 expression. Both combinations increased mitochondrial membrane permeability, correlating with increased cell death. Proteomic analysis of Met+Ven treated cells revealed decreased expression of core mitochondrial respiratory chain complex 1 protein (NDUFV1) and alterations in complex 4 proteins (increased COX5A, decreased NDUFA4). Additionally, endoplasmic reticulum proteins related to protein folding and ubiquitylation were upregulated, suggesting endoplasmic reticulum stress. These findings suggest that the Met+Ven combination could induce both ER and mitochondrial stress, leading to increased calcium flux and necroptosis, and could have clinical applications to patients who are ineligible for induction chemotherapy."]},{"key":"dc:title","label":"Title","values":["Investigating the metabolic impact of Metformin and Berberine in combination with Venetoclax for Acute Myeloid Leukaemia treatment"]}]}],"canonical_facts":{"dc:contributor":["Kris Jeremy, Vikram Sharma, Andrew Foey, Shagun Khera"],"dc:creator":["Robins, Samantha"],"dc:date.available":["2025-02-26T08:00:00Z"],"dc:date.issued":["2025-01-01T08:00:00Z"],"dc:description.abstract":["Acute myeloid leukaemia (AML) stands as a significant challenge in haematological malignancies, particularly due to poor outcomes in older patients and resistance to therapy. BCL-2, an anti-apoptotic protein, is overexpressed in AML. The BCL-2 antagonist Venetoclax inhibits OXPHOS and induces apoptosis in AML cells, which is potentiated when combined with Metformin an anti-hyperglycaemic agent used to treat type 2 diabetes, which also has anti-cancer properties. This study explored the effects of Venetoclax combined with Metformin or Berberine, an herbal supplement with a similar mechanism of action to metformin, on AML cell death and metabolic changes. The combination of Metformin and Venetoclax (Met+Ven) showed a synergistic cell death response in the HL60 cell line, unlike Berberine and Venetoclax (BBR+Ven). The combination treatments increased lactate production compared to their monotherapy, however Met+Ven increased lactate retention and reduced expression of the lactate efflux protein MCT4, whereas BBR+Ven increased MCT4 expression. Both combinations increased mitochondrial membrane permeability, correlating with increased cell death. Proteomic analysis of Met+Ven treated cells revealed decreased expression of core mitochondrial respiratory chain complex 1 protein (NDUFV1) and alterations in complex 4 proteins (increased COX5A, decreased NDUFA4). Additionally, endoplasmic reticulum proteins related to protein folding and ubiquitylation were upregulated, suggesting endoplasmic reticulum stress. These findings suggest that the Met+Ven combination could induce both ER and mitochondrial stress, leading to increased calcium flux and necroptosis, and could have clinical applications to patients who are ineligible for induction chemotherapy."],"dc:identifier":["https://pearl.plymouth.ac.uk/bhs-theses/22"],"dc:language":["eng"],"dc:title":["Investigating the metabolic impact of Metformin and Berberine in combination with Venetoclax for Acute Myeloid Leukaemia treatment"],"dc:type":["Thesis"]},"updated_at":"2026-07-24T03:49:35Z"}