Effects of schweinfurthin analogue 5’-methylschweinfurthin G in multiple myeloma cell lines
Restricted (Penn State Only)
- Author:
- Manfredi, Barbara
- Graduate Program:
- Biomedical Sciences
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- May 13, 2022
- Committee Members:
- Elizabeth Proctor, Outside Field Member
Kent Vrana, Major Field Member
Raymond Hohl, Chair & Dissertation Advisor
Barbara Miller, Outside Unit Member
Jeffrey Neighbors, Major Field Member
Ralph Keil, Program Head/Chair - Keywords:
- multiple myeloma
schweinfurthin G
5’-methylschweinfurthin G
cytotoxicity
natural product
MIP-1α
Golgi secretion
AKT
human-derived cell lines - Abstract:
- Multiple myeloma is a plasma cell cancer -that is characterized by excessive proliferation of plasma cells in the bone marrow, but also in extramedullary sites. The bones most frequently involved are vertebral spine, skull, pelvis, rib cage, and hips. Bones of the distal extremities are usually not affected. Despite some causes and risk factors having been identified, the exact etiology of the disease is not clear. Current therapeutic approaches exist, that have prolonged life expectancy of the patients with active myeloma disease, but come with side effects that lower life quality. Despite treatment options, this disease remains highly lethal and new therapies are needed. The contribution of natural products in cancer therapy has been fundamental, and the National Cancer Institute (NCI) has heavily invested in collection of natural products from various sources, especially terrestrial plants. Cytotoxicity screenings of organic extracts of Macaranga schweinfurthii leaves against cancer cell lines showed growth inhibition, especially in hematological tumors. This growth inhibition is due to the class of molecules that are termed schweinfurthins. The studies described in this dissertation have increased the understanding of the effects of schweinfurthins on malignant plasma cells. For this body of work, we have evaluated the molecular and cytologic effects of 5’-methylschweinfurthin G (MeSG), a schweinfurthin analogue, against multiple malignant plasma cell lines (RPMI-8226, MM.1S, and H-929). We observed that MeSG exerts its cytotoxic effect in vitro by decreasing cell viability and metabolic activity. We also interrogated the effects of MeSG on mitochondria functionality, as reflected in changes in membrane potential. The decreased cell viability caused by MeSG treatment can be explained by decreasing activation of the key survival signaling pathway involving AKT and by increasing oxidative stress measured as cytosolic reactive oxygen species. This unbalanced oxidative stress along with mitochondria dysfunctionality resulted in early DNA damage and cell cycle arrest, which ultimately leads to cell death via apoptosis. As myeloma is also characterized by immunoglobulin and cytokine secretion in the bone marrow environment, which supports its progression, we investigated the effect of MeSG on the secretion of a chemokine MIP-1α. Our data indicated that the secretory phenotype of the disease is only partially affected by MeSG in myeloma cell lines, with altered Golgi architecture and partial diminished chemokine secretion via the Golgi. It is interesting that the cell lines assayed for this project have mostly shown similar behaviors upon MeSG treatment, except for the RPMI-8226 line. Overall, we conclude that MeSG provides therapeutic efficacy in cell culture settings and supports further testing in in vivo models.