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Overcoming drug resistance in cancer cells with synthetic isoprenoids
Abstract:
A cultured subline (P388/ADM) of mouse P388 leukemia resistant to doxorubicin, vinblastine, vincristine, dactinomycin, and daunorubicin became sensitive again when treated with noncytotoxic doses of either of two synthetic isoprenoids: N-solanesyl-N,N'-bis(3,4-dimethoxybenzyl)ethylenediamine (SDB-ethylenediamine) and N-(p-methylbenzyl)decaprenylamine X HCI (PMB-decaprenylamine). The isoprenoids also reversed resistance to doxorubicin and vincristine in a cultured vincristine-resistant P388 leukemia subline (P388/VCR). Median lethal doses (LD50) for PMB-decaprenylamine and SDB-ethylenediamine administered ip were 123 and 350 mg/kg against mice, whereas the LD50 for verapamil, another modifier of cellular drug resistance, was about 7.6 mg/kg. In vivo experiments with P388/VCR-bearing mice showed that both SDB-ethylenediamine and verapamil overcame vincristine resistance, but PMB-decaprenylamine showed only slight activity. SDB-ethylenediamine was especially effective, overcoming the vincristine resistance at 1 mg drug/kg. Since the structure of SDB-ethylenediamine resembles that of verapamil, a calcium-blocking agent that overcomes drug resistance, it was checked for calcium-blocking activity. However, calcium channel-blocking activity was not observed with 20 micrograms isoprenoid/ml, whereas calcium channel activity was completely blocked by 1 microgram verapamil/ml.
Insights
Two synthetic isoprenoids, SDB-ethylenediamine and PMB-decaprenylamine, restored sensitivity to chemotherapy drugs in resistant leukemia cells. SDB-ethylenediamine effectively reversed drug resistance in vivo, unlike verapamil, without blocking calcium channels.
Area of Science:
- Biochemistry
- Pharmacology
- Cancer Research
Background:
- Multidrug resistance (MDR) is a major challenge in cancer chemotherapy, limiting the efficacy of various anticancer drugs.
- P-glycoprotein is a key transporter involved in MDR, actively pumping drugs out of cancer cells.
- Synthetic isoprenoids are being investigated for their potential to overcome MDR.
Purpose of the Study:
- To evaluate the ability of two synthetic isoprenoids, N-solanesyl-N,N'-bis(3,4-dimethoxybenzyl)ethylenediamine (SDB-ethylenediamine) and N-(p-methylbenzyl)decaprenylamine X HCI (PMB-decaprenylamine), to reverse multidrug resistance in cultured leukemia cells.
- To assess the in vivo efficacy of these isoprenoids in overcoming drug resistance in a mouse leukemia model.
Main Methods:
- Established drug-resistant sublines of mouse P388 leukemia (P388/ADM and P388/VCR).
- Treated resistant cells and P388/VCR-bearing mice with noncytotoxic doses of SDB-ethylenediamine and PMB-decaprenylamine.
- Administered median lethal doses (LD50) to assess in vivo toxicity.
- Compared the efficacy of isoprenoids with verapamil, a known MDR modulator.
- Assessed calcium channel-blocking activity of SDB-ethylenediamine.
Main Results:
- Both SDB-ethylenediamine and PMB-decaprenylamine restored sensitivity to multiple chemotherapy drugs in P388/ADM cells.
- These isoprenoids also reversed resistance to doxorubicin and vincristine in P388/VCR cells.
- In vivo, SDB-ethylenediamine and verapamil overcame vincristine resistance in P388/VCR-bearing mice, while PMB-decaprenylamine showed limited activity.
- SDB-ethylenediamine was highly effective, overcoming vincristine resistance at a low dose (1 mg/kg).
- SDB-ethylenediamine did not exhibit calcium channel-blocking activity at tested concentrations, unlike verapamil.
Conclusions:
- Synthetic isoprenoids, particularly SDB-ethylenediamine, show promise as agents to overcome multidrug resistance in leukemia.
- SDB-ethylenediamine's efficacy in vivo and lack of calcium channel-blocking activity suggest a distinct mechanism of action compared to verapamil.
- Further research into SDB-ethylenediamine could lead to novel therapeutic strategies for overcoming chemotherapy resistance.