Cancer drug resistance is a major challenge in effective cancer treatment. This study investigates whether resistance to chemotherapy arises from reduced cell proliferation or inhibition of cell death. Four cancer cell lines (A549, U1810, SKOV3, and SW620) were used to develop cisplatin-resistant cells using a pulse-selection approach, which mimics clinical chemotherapy conditions. The study combined various methods, including MTS assays, LIVE/DEAD assays, clonogenic assays, and Western blotting, to assess resistance mechanisms. The results showed that three cell lines (A549, U1810, and SKOV3) developed resistance primarily through modulation of proliferation and metabolism, avoiding the cytostatic effects of cisplatin. In contrast, SW620 cells became resistant to cell death, overcoming the cytotoxic effects. The study also found that SW620 cells remained sensitive to topotecan, indicating that resistance to one drug does not necessarily confer resistance to others. Biochemical analysis revealed that resistance mechanisms varied among the cell lines. For example, SW620 cells showed increased resistance to apoptosis, while others exhibited changes in autophagy and ferroptosis. Metabolic analysis showed that SW620 cells maintained higher metabolic activity compared to other resistant lines. The study concludes that resistance to chemotherapy can arise through different mechanisms, and a combination of methods is necessary to fully understand these mechanisms. The findings highlight the importance of assessing both cell death and proliferation in evaluating drug resistance. The study provides a framework for analyzing resistant cell lines, emphasizing the need for a comprehensive approach to understand and overcome drug resistance in cancer therapy.Cancer drug resistance is a major challenge in effective cancer treatment. This study investigates whether resistance to chemotherapy arises from reduced cell proliferation or inhibition of cell death. Four cancer cell lines (A549, U1810, SKOV3, and SW620) were used to develop cisplatin-resistant cells using a pulse-selection approach, which mimics clinical chemotherapy conditions. The study combined various methods, including MTS assays, LIVE/DEAD assays, clonogenic assays, and Western blotting, to assess resistance mechanisms. The results showed that three cell lines (A549, U1810, and SKOV3) developed resistance primarily through modulation of proliferation and metabolism, avoiding the cytostatic effects of cisplatin. In contrast, SW620 cells became resistant to cell death, overcoming the cytotoxic effects. The study also found that SW620 cells remained sensitive to topotecan, indicating that resistance to one drug does not necessarily confer resistance to others. Biochemical analysis revealed that resistance mechanisms varied among the cell lines. For example, SW620 cells showed increased resistance to apoptosis, while others exhibited changes in autophagy and ferroptosis. Metabolic analysis showed that SW620 cells maintained higher metabolic activity compared to other resistant lines. The study concludes that resistance to chemotherapy can arise through different mechanisms, and a combination of methods is necessary to fully understand these mechanisms. The findings highlight the importance of assessing both cell death and proliferation in evaluating drug resistance. The study provides a framework for analyzing resistant cell lines, emphasizing the need for a comprehensive approach to understand and overcome drug resistance in cancer therapy.