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سلول و بافت، جلد ۱۶، شماره ۲، صفحات ۱۳۲-۱۵۵
عنوان فارسی بررسی تاثیر مسدودکننده‌های کانال‌ کلسیم بر سمیت سلولی دوکسوروبیسین در رده‌ها‌ی سلولی سرطان پستان MDA-MB-۲۳۱ و MCF-۷
چکیده فارسی مقاله هدف: هدف این مطالعه ارزیابی تاثیر ترکیبی دو داروی مسدودکننده­ی کانال­ کلسیمی شامل آملودیپین و دیلتیازم بر سمیت دوکسوروبیسین در رده­های سلولی سرطان پستان است. مواد و روش‫ها: سلول­های MDA-MB-231 و MCF-7 با غلظت­های مختلف آملودیپین، دیلتیازم به‫صورت تکی و در ترکیب با دوکسوروبیسین به‫مدت 48 و 72 ساعت تیمار شدند. بقای سلولی با تست MTT بررسی شد. مقادیر IC50 از منحنی دوز-پاسخ، محاسبه شد. اثر ترکیبی داروها با محاسبه شاخص ترکیبی (CI) مورد بررسی قرار گرفت. فعالیت کاسپاز-3/7 به‫عنوان نشانگر القای آپوپتوزیس با روش سنجش آنزیمی مبتنی بر سوبسترای رنگ­زا (Ac-DEVE-pNA) در لیز سلول­های تیمارشده  اندازه­گیری شد. نتایج: نتایج نشان داد که آملودیپین و دیلتیازم با برابر با  اثر مهاری بر تکثیر سلول­های سرطانی MDA-MB-231 و MCF-7 به‫صورت وابسته به غلظت و زمان دارند. ارزیابی فعالیت کاسپاز-3/7 در لیز سلول‌های تیمارشده با داروها نشان داد که آملودیپین باعث افزایش فعالیت کاسپاز-3/7 در هر رده­ی سلولی می‌شود که نشان‌دهنده القای آپوپتوزیس است. در سلول‌های تیمارشده با دیلتیازم، فعالیت کاسپاز-3/7 تنها در سلول‌های MCF-7 مشاهده شد، در حالی‫که فعالیت کاسپاز-3/7 در سلول‌های MDA-MB-231 کم‫تر از کنترل بود که نتیجه­گیری در این خصوص نیازمند مطالعات بیشتر است. مقدار CI ، در اکثر غلظت­ها بزرگ‌تر از یک بود که نشان‌دهنده تداخل آملودیپین و دیلتیازم با اثر سیتوتوکسیک دوکسوروبیسین در طیف وسیعی از غلظت‌ها است. نتیجه­گیری: آملودیپین و دیلتیازم نه تنها قادر به القای مرگ سلولی در سلول­های سرطانی هستند، بلکه در غلظت­های پائین در اثر سیتوتوکسیک دوکسوروبیسین تداخل ایجاد می­کنند. این نتایج اهمیت بررسی تعاملات دارویی مسدودکننده‌های کانال کلسیمی با شیمی‌درمانی را برجسته می‌سازد.
کلیدواژه‌های فارسی مقاله آملودیپین،سرطان پستان،مسدودکننده‌های کانال‌ کلسیمی،شیمی‌درمانی،دیلتیازم،
عنوان انگلیسی Assessing the Impact of Calcium Channel Blockers on Doxorubicin-Induced Cytotoxicity in MDA-MB-231 and MCF-7 Breast Cancer Cell Lines
چکیده انگلیسی مقاله Introduction: Breast cancer is the second leading cause of cancer-related mortality in women. Breast cancer is a multi-step process involving various types of cells, and its prevention remains a global challenge. One of the best ways to prevent breast cancer is through early detection. The upregulation of calcium channels is associated with the proliferation and progression of cancer cells, including breast cancer. The calcium channel blockers are a chemically heterogeneous group that prevents the entry of calcium into the muscle cells of blood vessels and the heart. It has been demonstrated that calcium channel blockers exhibit cytotoxic effects on various types of cancer. Doxorubicin is a well-established chemotherapeutic agent used in the treatment of cancer. Two commonly used calcium channel blockers are amlodipine and diltiazem. However, their interactions with common chemotherapeutic agents such as doxorubicin, which face limitations of cardiotoxicity and cellular resistance, have not been fully investigated.
Aims: This study aimed to evaluate the combined effects of two calcium channel blockers, including amlodipine and diltiazem, on doxorubicin cytotoxicity in breast cancer cell lines.
Materials and Methods: Different concentrations of amlodipine and diltiazem were prepared. Their effects were evaluated both alone and in combination with low concentrations of doxorubicin (which showed minimal cytotoxic effects) on cell proliferation and survival of MDA-MB-231 and MCF-7 human breast cancer cell lines at 48 and 72 hours using the MTT assay. The MTT assay is a colorimetric test that assesses cell metabolic activity. It measures the reduction of MTT, a yellow tetrazole, to purple formazan by mitochondrial enzymes in viable cells. The amount of formazan produced is directly proportional to the number of living cells, making it a useful method for evaluating cell viability and proliferation. Apoptosis is a programmed cell death process that plays a critical role in maintaining tissue homeostasis and eliminating damaged or unwanted cells. Caspase-3/7 activity in drug-treated cell lysates was evaluated to assess apoptosis. All tests were performed at least three times. Differences between samples were analyzed using the t-test and one-way ANOVA, and curves were plotted using Microsoft Excel.
Results: The results of this study demonstrated that both amlodipine and diltiazem inhibited the proliferation of MDA-MB-231 and MCF-7 cancer cells in a concentration- and time-dependent manner. Evaluation of caspase-3/7 activity in the cells treated with amlodipine revealed an increase in caspase-3/7 activity in both cell lines, indicating the induction of apoptosis. In cells treated with diltiazem, caspase-3/7 activity was observed only in MCF-7 cells, while the activity of caspase-3/7 in MDA-MB-231 cells was lower than the control group. Investigating the cytotoxic effect of doxorubicin in the presence of amlodipine and diltiazem showed that these drugs interfered with most cytotoxic concentrations of doxorubicin.
Discussion: The results of this study showed that increasing the concentration of amlodipine and diltiazem, as well as extending the treatment duration, caused cell death in both MDA-MB-231 and MCF-7 cell lines. Caspase-3 and -7 act as executioner enzymes in apoptosis (programmed cell death). The increased activity of caspase 3/7 in MDA-MB-231 and MCF-7 cells treated with amlodipine suggests that amlodipine can induce apoptosis through caspase-dependent pathways. Similarly, increased caspase 3/7 activity was observed in MCF-7 cells treated with diltiazem. However, in MDA-MB-231 cells treated with diltiazem, caspase activity was significantly lower compared to the control group. This unexpected result may indicate that diltiazem induces cell death independently of caspase 3/7 in this cell line, but further experiments are needed to definitively confirm this hypothesis. Calcium is an important regulator of many essential cellular functions and generally acts as a mitogen to stimulate growth in most proliferating cells. It has been reported that tumors typically have abnormally high calcium levels, due to excessive influx of extracellular calcium or the ability of cancerous mitochondria to maintain higher calcium concentrations.  The high levels of intracellular calcium production may activate the calcium second messenger cascade, promoting the overgrowth of certain malignant cells. Human breast cancer cell lines HT-39 and MCF-7, the human promyelocytic leukemia cell line HL-60, and the leukemia cell line L1210, have shown calcium-dependent proliferation. Okazaki et al.  confirmed these findings and demonstrated that the HL-60 cells grow in a manner dependent on extracellular calcium. Additionally, Yonda et al. showed that the growth of a breast cancer cell line (VX2) is tightly regulated by extracellular calcium levels. However, other studies have that removing calcium from the growth medium of some tumorigenic cell lines, such as transformed fibroblasts, hepatic hematomas, mouse embryonic 3T3 cells, and human ovarian cells, does not affect their growth. Therefore, the role of calcium in cell death and proliferation is complicated. Doxorubicin is a widely used chemotherapy drug for breast cancer. Given the high prevalence of hypertension worldwide, cancer patients undergoing chemotherapy often use calcium channel blockers like amlodipine and diltiazem to control blood pressure. Given that amlodipine and diltiazem can induce cancer cell death by blocking calcium channels, this study investigated the cytotoxic effect of doxorubicin in the presence of low concentrations of these drugs on both cell lines. The results showed that amlodipine significantly affected the cytotoxic effect of doxorubicin. This effect depends on concentration and treatment duration. At lower concentrations, amlodipine reduced doxorubicin-induced cell death, and at higher concentrations, due to increased doxorubicin levels, it could not inhibit the drug's toxic effects. Diltiazem is another calcium channel blocker used to lower blood pressure. It has been reported that diltiazem is less potent in lowering blood pressure than amlodipine. Diltiazem also had similar effects to amlodipine. It had antagonistic effects on doxorubicin cytotoxicity at different concentrations and depending on the duration of treatment. Diltiazem, a calcium channel blocker, is known as a P-gp (P-glycoprotein) inhibitor, which reduces cardiotoxicity caused by chemotherapeutic agents. Further studies are needed to explore the underlying mechanisms and therapeutic implications of these findings.
Conclusion: Amlodipine and diltiazem not only induce cell death in cancer cells but also interfere with the cytotoxic effects of doxorubicin at low concentrations. These results highlight the importance of investigating drug interactions between calcium channel blockers and chemotherapeutic agents.
کلیدواژه‌های انگلیسی مقاله آملودیپین,سرطان پستان,مسدودکننده‌های کانال‌ کلسیمی,شیمی‌درمانی,دیلتیازم
نویسندگان مقاله الهام قادری |
کارشناس‌ارشد، گروه علوم زیستی، دانشکده علوم پایه، دانشگاه کردستان، سنندج، ایران، elhamghaderi8@gmail.com

راحله شاکری |
استادیار، گروه علوم زیستی، دانشکده علوم پایه، دانشگاه کردستان، سنندج، ایران، r.shakeri@uok.ac.ir

نشانی اینترنتی https://jct.araku.ac.ir/article_728842_2583ae4cb9fe0a5908dac9954fa05938.pdf
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