Solid tumors usually have a complex cellular components and intercellular interactions in a complex tumor microenvironment. We used a mathematical HK model to predict the change of drug resistance to cisplatin in a mixed sensitive and resistant human cervical cancer cell population and then employed a cytosensitivity assay to evaluate if biological findings could confirm this change predicted by HK model.
We used the HK model to predict the resistance to cisplatin in the mixed cell population. To confirm this prediction, we mixed the sensitive and resistant cancer cells and studied their resistance to cisplatin. Separate sensitive and resistant cells were also set up as controls. Two human cervical cancer cells 2008 (sensitive) and 2008/C13*(resistant) were grown in RPMI 1640 medium supplemented with 10% FBS. The cytosensitivity was evaluated with MTT assay.
Based on HK model, our hypothesis was that after mixing the two cell lines with different resistance, due to intercellular connection and communication ("talking" &"opinion change"), the resistant cells would instigate the sensitive cells to become more resistant, and therefore, the mixed population would show a different property with more resistance. We mixed the same amounts of sensitive and resistant cancer cells and treated them with cisplatin and compared with their corresponding IC50s of parental cells. In different cell number groups of 1000, 2000, 4000, and 6000 cells, the ratios of the mixed cell population IC50s over the average IC50s of sensitive and resistant cells, showed the same tendency. Namely, with the longer incubation period from day 2 to day 7, the ratios consistently became increased at evey cell number group, which perfectly implied the increasing resistance to cisplatin in the mixed cell populations. In other words, after mixing the cells, the sensitivity of the mixed cell population was not as simple as the average of sensitive and resistant cells, but showed more resistant, which was interestingly compatible with the HK model prediction.
For the first time, with a HK model we correctly predicted the increased drug resistance in a mixed cancer cell population, which was demonstrated by our biological experiments in vitro. Based on these findings, we see here that the mathematical HK model can be employed to lift our vision up with novel idea in the research of chemoresistance field. The underlying mechanism is open for further exploration.