Disulfiram and disulfiram-loaded poly-[lactide-co-glycolic acid] nanoparticles modulate metastatic markers and proteasomal activity in hepatocarcinoma Hep3b cell line
Abstract
Hepatocellular carcinoma (HCC) results in significantly high mortality rates due to its subtle metastatic expressions. Exorbitant costs of anticancer drugs have lead to the concept of repositioning standard drugs for their anticancer potential. One such antialcoholic drug, disulfiram (DSF), has been reported to show significant cytotoxicity (IC 50 6 μM) against hepatocarcinoma cells. Hence, we studied its antimetastatic and proteasome-inhibiting potential to ascertain its efficacy against metastatic hepatocarcinoma. In addition, we also studied the influence of the components of polysorbate 80-stabilised poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) on metastastatic markers and proteasome complexes. A significant reduction in antimigratory assays (0.1 μM) and gelatin zymography (0.5 μM) was observed. A Western blot analysis furthermore confirmed the modulation of metastatic markers. Chymotrypsin-like activity was significantly inhibited at 2 μM of DSF, and in silico docking studies show comparable gliding scores of DSF against standard antimetastatic drugs. Our experiments suggest a significant antimetastatic and proteasome-inhibiting potential of DSF and its loaded NPs. We also infer that polysorbate 80 and PLGA neither show interference with drug behaviour nor inhibit metastasis and proteasome activity, thus behaving as components of a neutral vector. However, they may potentially manipulate the pharmacokinetics of DSF for achieving maximum therapeutic efficacy, in addition to targeted drug delivery.
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Antimetastatic potential of DIS is attributed to inhibition of cyclooxygenase-2, an important inflammatory marker.
“Antimetastatic potential of DIS is attributed to the inhibition of cyclooxygenase-2 (COX2), which is an important inflammatory marker, and inflammation is known to be closely associated with tumor development, metastasis, and invasion.60”
From Off-label and repurposed use of disulfiram beyond alcohol dependence: A systematic review of clinical and preclinical evidence (2026) · cites this paper as [60]
DIS directly inhibits matrix metalloproteinase enzymes by quenching their zinc cofactor, thereby overcoming TIMP2-mediated activation of pro-MMP2.
“On the other hand, DIS directly inhibits matrix metalloproteinase (MMP) enzymes by quenching their zinc cofactor, thereby overcoming tissue inhibitor 2 (TIMP2)-mediated activation of pro-MMP2.”
From Off-label and repurposed use of disulfiram beyond alcohol dependence: A systematic review of clinical and preclinical evidence (2026) · cites this paper as [60]
Several mechanisms have been reported for the induction of apoptosis by disulfiram in cancer cells, including inhibition of proteasome activity, regulation of transcription factors (e.g., NF-κB), activation of JNK signaling, and activation of the mitochondria-related intrinsic apoptotic pathway.
“In addition to ROS generation,58 several mechanisms have been reported for the induction of apoptosis by DIS in cancer cells, including the inhibition of proteasome activity,59,60 regulation of transcription factors [e.g., nuclear factor-kappa B (NF-κB)],61,62,63,64 activation of the stress-related c-Jun N-terminal kinases (JNK) signaling pathway65,66 and activation of the mitochondria-related”
From Off-label and repurposed use of disulfiram beyond alcohol dependence: A systematic review of clinical and preclinical evidence (2026) · cites this paper as [60]
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- Authors
- Hoda, M., Cavuturu, B. M., Iqbal, S., Shakya, G., & Rajagopalan, R.
- Affiliations
- Pondicherry University (IN)
- University of Madras (IN)
- Corresponding author
- Rajagopalan, Rukkumani
- Venue
- European Journal of Nanomedicine
- Publisher
- Walter de Gruyter GmbH
- Published
- 2017-10-01
- Volume
- 9
- Issue
- 3-4
- Pages
- 127-138
- ISSN
- 1662-596X (ISSN-L)
- 1662-5986
- OpenAlex
- W2771285466
- Cited by
- 3
- References
- 31
- Citations by year
- 2026: 1 · 2025: 1 · 2020: 1
- FWCI
- 0.10
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- European Journal of Nanomedicine (publishedVersion)
- Topics
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Keywords
- disulfiram, hepatocellular carcinoma, metastasis, PLGA nanoparticles, drug repurposing, proteasome inhibition, chymotrypsin-like activity, Hep3B cells, cell migration, gelatinase activity, Tween 80, drug delivery, molecular docking
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