Reversin 121
Also known as: P-gp inhibitor peptide 121, Reversin-121
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Summary
Reversin 121 (also called P‑gp inhibitor peptide 121) is a short, high‑affinity peptide that blocks the activity of the ATP‑binding cassette transporter P‑glycoprotein (P‑gp, MDR1). It is investigated as a research‑grade chemosensitizer intended to reverse multidrug resistance (MDR) in cancer cells, thereby improving the efficacy of conventional chemotherapeutics such as doxorubicin. Pre‑clinical work also shows tumor‑growth reduction in mouse pancreatic cancer models and potentiation of proteasome‑inhibitor activity in resistant blood cells.
Mechanism of Action
Reversin 121 binds directly to the transmembrane domain of P‑gp with nanomolar affinity (≈77–154 nM) as demonstrated by fluorescence quenching of purified protein. The peptide stimulates the ATPase activity of P‑gp at low micromolar concentrations, a pattern similar to classic chemosensitizers, and at higher concentrations can inhibit ATP hydrolysis. By occupying a site distinct from the Hoechst‑33342 (H) and daunorubicin (R) transport sites, it acts as a non‑competitive inhibitor, blocking the efflux of diverse substrates (e.g., colchicine, rhodamine 123, calcein AM) and restoring intracellular drug accumulation.
What the Research Shows
In vitro studies (Sharom et al., 1999) showed that reversin 121 binds P‑gp with high affinity, stimulates its ATPase, and blocks efflux of colchicine, daunorubicin and rhodamine 123, restoring drug uptake without harming P‑gp‑negative cells. An orthotopic mouse pancreatic‑cancer model (Hoffmann et al., 2008) demonstrated that adding reversin 121 to chemotherapy reduced P‑gp, MRP1 and MRP3 expression, decreased tumor size and metastasis. Ex vivo blood‑cell assays (Verbrugge et al., 2012) reported that reversin 121 restored sensitivity to proteasome inhibitors in cells overexpressing P‑gp. Polymer‑conjugate work (Biomacromolecules 2014; J Control Release 2016) attached reversin 121 to HPMA copolymers, achieving dose‑dependent 10‑ to 84‑fold increases in doxorubicin or pirarubicin cytotoxicity against resistant leukemia and neuroblastoma lines, especially when the inhibitor and drug were delivered together.
Reported Benefits
Reversin 121 restores sensitivity of P‑gp‑expressing cancer cells to a range of chemotherapeutics, including doxorubicin, daunorubicin and proteasome inhibitors, leading to markedly lower IC50 values. In mouse pancreatic‑cancer models it reduces tumor burden and metastasis. When incorporated into HPMA polymer carriers, it synergistically enhances drug cytotoxicity up to 84‑fold, and it shows no toxicity toward P‑gp‑negative control cells in vitro.
Limitations of the Evidence
All data are pre‑clinical; no human trials have been reported. Efficacy depends on concentration and often requires polymer conjugation for maximal effect. The peptide’s activity varies between cell lines and may be limited by off‑target interactions that have not been explored. Because it is not an approved drug, regulatory status, pharmacokinetics and optimal dosing remain unknown.
Safety Considerations
In vitro and animal studies reported no cytotoxicity of reversin 121 toward cells lacking P‑gp, and mouse experiments did not describe overt adverse effects. Ex vivo blood‑cell work showed restored drug activity without reported toxicity. However, safety in humans has not been evaluated, and potential interactions with other P‑gp substrates cannot be excluded. Caution is warranted until formal toxicology studies are performed.
How It Is Administered
Reversin 121 has been used in cell‑culture assays, injected into mice in orthotopic tumor models, and chemically linked to N‑(2‑hydroxypropyl)methacrylamide (HPMA) polymers via pH‑sensitive hydrazone spacers for controlled release. No approved formulation exists; routes are experimental (intravenous or intraperitoneal injection in animals, or direct addition to culture media).
Routes of Administration
Goals & Uses
- Reversal of multidrug resistance in cancerOncology / Pharmacology ResearchLow
- Increased intracellular accumulation of chemotherapeuticsDrug Delivery / Pharmacokinetics ResearchLow
Contraindications
- Human clinical useRegulatoryHigh
Adverse Effects
- Unknown systemic toxicityGeneralUnknown
Drug Interactions
- P-glycoprotein substrates (e.g., doxorubicin, vinblastine, paclitaxel)High
Population Constraints
- General human populationRegulatory/safetyAbsolute
Regulatory Status
- European UnionUnapprovedNo EMA filing; research use only.
- United StatesUnapprovedNo IND or regulatory filing; research use only.
- United KingdomUnapprovedNo MHRA filing; research use only.
No regulatory filings identified in any jurisdiction. Strictly a research/in vitro tool compound.
Evidence & Sources
- Journal ArticleLowSubr V, et al.2014-01-01T00:00:00.000000Z
- Journal ArticleLowHoffmann K, et al.2008-01-01T00:00:00.000000Z
- Journal ArticleLowSharom FJ, et al.1999-01-01T00:00:00.000000Z
- Journal ArticleModerateVerbrugge SE, et al.2012-01-01T00:00:00.000000Z
- Journal ArticleLowArnaud O, et al.2010-01-01T00:00:00.000000Z
- Journal ArticleLowKoziolová E, et al.2016-01-01T00:00:00.000000Z
Frequently Asked Questions
What is reversin 121?
Reversin 121 is a short synthetic peptide that binds the multidrug‑resistance transporter P‑glycoprotein with high affinity and blocks its drug‑efflux function, making it a research‑stage chemosensitizer.
How does reversin 121 work to reverse drug resistance?
The peptide attaches to P‑gp, stimulates its ATPase at low concentrations and blocks substrate transport by acting as a non‑competitive inhibitor at a site distinct from the classic drug‑binding pockets, thereby increasing intracellular concentrations of chemotherapeutic agents.
Has reversin 121 been tested in humans?
No. All published evidence is limited to cell‑culture experiments, polymer‑conjugate studies, and mouse tumor models. It has not been evaluated in clinical trials and is not an approved medication.
Can reversin 121 be used together with standard chemotherapy?
Pre‑clinical data show that combining reversin 121 with drugs such as doxorubicin or proteasome inhibitors markedly improves their cytotoxicity in resistant cells, but because human safety and dosing are unknown, it cannot be used clinically at this time.
What are the known safety concerns?
In vitro and animal work reported no toxicity to P‑gp‑negative cells and no overt adverse effects in mice, but comprehensive toxicology, immunogenicity and interaction studies in humans have not been performed, so safety remains uncharacterized.
What is Reversin 121 used for?
Reversin 121 is educationally associated with: Reversal of multidrug resistance in cancer, Increased intracellular accumulation of chemotherapeutics. Educational only — not medical advice.
How is Reversin 121 administered?
Recorded routes of administration: In Vitro.
What are the potential side effects of Reversin 121?
Reported adverse effects include: Unknown systemic toxicity. This list is not exhaustive — consult a qualified clinician.
Who should avoid Reversin 121?
Recorded contraindications: Human clinical use. Consult a qualified clinician before use.