Enhancing activity and overcoming chemoresistance in hematologic malignancies with bortezomib: preclinical mechanistic studies.
BACKGROUND
Proteasome inhibition results in antitumor activity through various mechanisms, including disruption of cell cycle progression and control, induction of apoptosis, and inhibition of proliferation.


METHODS
This review assesses preclinical data on the ability of bortezomib, the first proteasome inhibitor approved for clinical use, to enhance antitumor activity of other agents and to overcome chemoresistance in hematologic malignancies and discusses mechanisms by which such activity arises.


RESULTS
Bortezomib has been shown to affect multiple cellular pathways and levels of numerous intracellular proteins, including targets of importance in hematologic malignancies. These mechanisms have shown additive or synergistic effects in vitro and in vivo with those of conventional therapeutic and novel targeted agents. Additionally, targets of proteasome inhibition are implicated in resistance or lack of sensitivity to different therapies. Bortezomib in combination with other agents has been shown to overcome resistance to those agents and to resensitize cells to agents to which they were previously unresponsive.


CONCLUSIONS
This review indicates the potential utility of proteasome inhibition for substantially enhancing activity of other therapeutic approaches. It explains the mechanisms responsible for the observed clinical activity of bortezomib-based regimens and elucidates novel therapeutic approaches through identification of combinations of agents with complimentary mechanisms of action.
Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA.
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Reddy
Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA. Electronic address: myron.czuczman@roswellpark.org.
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Czuczman
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001897:Boronic Acids / Q000627:therapeutic use*; D000069286:Bortezomib; D002986:Clinical Trials as Topic; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D019337:Hematologic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D011719:Pyrazines / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D001897:Boronic Acids; D011719:Pyrazines; D000069286:Bortezomib