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Thermosensitivity of multidrug-resistant human gastric and pancreatic carcinoma cells
1Institute of Pathology, Humboldt University Berlin, Germany. hermann.lage@charite.de
Abstract:
Often, tumour cells acquire drug resistance phenotypes, which include the classical multidrug resistance (MDR) phenomenon accompanied by the synthesis of the P-glycoprotein (Pgp) and atypical MDR phenotypes mediated by different, in part unknown, mechanisms. To investigate the susceptibility of tumour cells exhibiting different kinds of MDR to treatment with heat, the hyperthermic survival of established human gastric and pancreatic carcinoma cell lines were studied and sublines exhibiting a classical and an atypical MDR phenotype were derived, respectively. Arrhenius analysis of this panel of gastrointestinal tumour cells revealed that both the classical and the atypical MDR variants exhibited no breaking points (T*) in contrast to the parent tumour cells. The activation enthalpies E(A) were about 40% lower at T > T* in comparison to the E(A) at lower temperatures. Classical MDR variants of both gastrointestinal tumour cell types exhibited a similar E(A) value, whereas the E(A) of atypical MDR gastric carcinoma cells was 1.6-fold higher than the E(A) of corresponding pancreatic carcinoma cells. In comparison to the parent lines, the drug resistant variants exhibited a 2.1-fold (gastric carcinoma, classical MDR), 2.7-fold (gastric carcinoma, atypical MDR) and 1.4-fold (pancreatic carcinoma, classical MDR) increase of activation enthalpies and a nearby unchanged E(A) in pancreatic carcinoma cells exhibiting an atypical MDR.
Insights
Tumor cells with multidrug resistance (MDR) show altered heat sensitivity. Both classical and atypical MDR variants displayed unique thermal resistance patterns, impacting treatment strategies for gastrointestinal cancers.
Area of Science:
- Oncology
- Cell Biology
- Biophysics
Background:
- Tumor cells frequently develop multidrug resistance (MDR), involving P-glycoprotein (Pgp) or other mechanisms.
- Understanding MDR variants' response to hyperthermia is crucial for cancer treatment.
Purpose of the Study:
- To investigate the hyperthermic survival of human gastric and pancreatic carcinoma cell lines with classical and atypical MDR phenotypes.
- To analyze thermal resistance using Arrhenius analysis.
Main Methods:
- Established human gastric and pancreatic carcinoma cell lines were used.
- Sublines with classical and atypical MDR were derived.
- Hyperthermic survival and Arrhenius analysis were performed.
Main Results:
- Both classical and atypical MDR variants lacked thermal breaking points (T*) seen in parent cells.
- Activation enthalpies (E(A)) were approximately 40% lower at higher temperatures.
- Atypical MDR gastric cells had a 1.6-fold higher E(A) than atypical MDR pancreatic cells.
Conclusions:
- MDR phenotypes significantly alter tumor cell responses to hyperthermia.
- Distinct MDR mechanisms influence thermal resistance profiles.
- Findings suggest potential for targeted hyperthermia in MDR cancers.
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