Mechanism of Anticancer drug Resistance and Therapeutic approaches for overcoming resistance

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SEMINAR-I
Mechanism of Anti-Cancer Drug Resistance and
Therapeutic Approaches for Overcoming
Resistance
Submitted to : Submitted by:
Dr. Viney Lather Firuj Ahmed
Professor & Centre Head - Pharmaceutical Chemistry & M.Pharm 1st year
Pharmaceutical Analysis, AIP Enrolment No.:A10655022001
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CONTENT
1. INTRODUCTION
2. TYPES OF TUMORS
3. TREATMENT OF CANCER
4. PROBLEM WITH THE CHEMOTHERAPY CANCER DRUGS
5. NEED FOR STUDYING ANTICANCER DRUG RESISTANCE
6. DRUG RESISTANCE
7. TEST TO DETERMINE ANTICANCER DRUG RESISTANCE
8. THERAPEUTIC APPROACHES TO OVERCOME RESISTANCE
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DEFINITION: Cancer is characterized by the uncontrolled growth of
cells which tend to proliferate in an uncontrolled way. In medical
science cancer or tumor is known as neoplasm.
Not all tumors are cancerous; tumors are of two types:
1. Benign
2. Malignant
1. BENIGN TUMOR: Benign tumors are those which does not spread
into any other part of the body.
2. Malignant tumors: These are cancerous cells. Cells in this tumor
can damage nearby cells of the tissue and can spread to the other
part of the body. The process of spreading cancer from one body
part to another is called metastasis.
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Treatment of cancer: There are various ways through which that
cancer can treat, which are given below:
1. Chemotherapy
2. Radiotherapy
3. Hormone Therapy
4. Gene Therapy
5. Immunotherapy
6. Surgery
Problems with the Chemotherapy Cancer drugs:
Anticancer agents are nothing, just toxins that are used to kill cancer
cells, so the cancer cells have an inbuilt mechanism to protect
themselves from the toxins.
This can give rise to the formation of resistance to the anticancer
Medication curating cancer.
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NEED FOR STUDYING ANTICANCER DRUG RESISTANCE:
After cardiovascular diseases cancers are the second biggest cause of
death globally. So studying its origin, causes, factors, propagation,
mechanisms, and cure is very important.
As we know, when a drug is used for a long period it can produce
resistance over time. So, to overcome this problem studying anticancer
drug resistance is also very important.
DRUG RESISTANCE:
Resistance is the decrease in the effectiveness of the drug due to
different mechanisms.
Drug resistance can be reduced by a combination of different drugs.
Anticancer Drug resistance:
The concept of drug resistance comes under to know when some
bacteria show resistance to antibiotics, later similar mechanisms are
found in other diseases which, include cancer.
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Initially, almost every type of cancer is defenseless against
chemotherapy treatment, but over time, this drug developed resistance
to the anti-cancer medication through different types of mechanisms.
Categories of the mechanism through which cancer cells developed
resistance to the anti-cancer medication
1. Drug inactivation
2. Drug target alteration
3. Drug efflux
4. DNA damage repair
5. Cancer Cell Heterogeneity
6. Cell death inhibition
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MECHANISM OF DRUG RESISTANCE IN CANCER CELLS
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DRUG INACTIVATION:
• Activation of the drug molecules is an in-vivo process, in this process
the drug interacts with different types of proteins. This interaction
causes modification, and complex formation with different types of
proteins or different types of molecules, which causes the activation of
these agents.
• This anticancer drug may go through metabolic activation. However,
the cancer cells produce resistance to this type of mechanism, which
causes a decrease in the activation of these agents.
• Example: When Cytarabine is used in the treatment of Chronic
Myeloid Leukemia; this is the medicine which is operate after several
times of phosphorylations, which results in the formation of
Cytarabine-triphosphate.
• This expedites a lowering of the mobilization of Cytarabine in this
pathway, which induces Cytarabine resistance.
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Alteration of Drug Target:
• The molecular target is the most salient feature for the optimum
activity of the drug molecule, while the alterations of this drug target by
mutation or modification can lead to failure of the treatment by the
anticancer agents.
• The therapeutic potential of a drug molecule is controlled by the
alterations of its site of action and its molecular targets, such as
mutation of the cell in the body. In cancer cells, these types of
changes in the molecular target can directly give rise to the resistance
of the drug molecule.
Efflux of the drug molecule:
• Drug efflux is another very important mechanism of resistance of the
drug molecules. In this mechanism, cancer-causing cells do not let the
drug accumulate in the cell at the desired concentration to its effect
which leads to the failure of the therapy.
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Increased ability to repair DNA damage:
• The restoration of destructed DNA has a vital role in the resistance of
anti-cancer drugs. The cell nature or mechanism of the damage DNA
repair leads to produce drug resistance in chemotherapy, and the DNA
damage repair mechanism of the cell can reverse the damage
produced by the drug to the cancer cells in chemotherapy which lead to
producing its resistance.
• Example: Chemotherapeutic agents containing platinum, like cisplatin,
that attack the DNA cross-linked cause apoptosis. The resistance of this
arises due to nucleotide homologous recombination, which leads to the
repair of the primary damage of DNA and it causes the failure of the
treatment of the anticancer drugs which produce drug resistance and
inhibit the therapeutic effect of the anticancer agents.
Cancer Cell Heterogeneity:
• In this type of mechanism, the cancer cells which are already resistant
to the anticancer drug increased their growth.
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• Research indicates that some of the heterogeneous present in
cancer cells have stem cell-like properties that are typically drug-
resistant and these cells start producing cells that are born with
anticancer-resistant properties.
Cell death inhibition:
• Apoptosis and autophagy are two crucial regulatory processes
that cause cell death. Both pathways lead to cell death, even
though they are mutually exclusive.
• Apoptosis is work through two different pathways:
1. One of the pathways is intrinsic which is conciliated through the
mitochondria that involve the BCL-2 family, cascade-9, and Akt.
2. The other mechanism is extrinsic and involves the death receptor
on the surface of the cells.
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TEST TO DETERMINE ANTICANCER DRUG RESISTANCE
• Not all patients need to be resistant to a particular anticancer drug.
• Some tumors may be highly resistant to a particular drug or some may
be quite sensitive.
• Therefore, it would be useful to have some tests, which could predict
resistance and subsequent clinical failure.
• This would relieve the patients from the trauma of ineffective
chemotherapeutic treatment.
• A company called IMPATH has developed a cell culture drug
resistance assay, which they claim can help in the selection of
chemotherapeutic drugs that have the greatest likelihood of being
clinically effective.
THERAPEUTIC APPROACHES TO OVERCOME RESISTANCE
NANOMEDICINE:
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• Nanomedicine is a new type of treatment that focuses on improving the
effectiveness of the medication while minimizing negative side effects
on healthy tissues.
• To enhance medication distribution, boost therapeutic efficacy, lessen
adverse effects, and combat drug resistance in anticancer therapy,
nanomedicines are being studied.
TREATMENT
• The nanoparticle connects to the tumor cell after safely passing
through the circulation. Near-infrared light, which is safe for humans
but only penetrates human tissue by around 1.5 inches, is used for the
majority of work.
• Nanoparticles are adjusted to be activated only at a specific range of
light, they may be heated up using the photothermal ablation concept.
• Normal cells died at about 46 °CC (115 °FF), but cancer cells died at
42 °CC (108 °FF).
• The impacts are often violent for smaller particles like cells and then
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CLASSES OF CANCER-FIGHTING NANOMEDICINE AND THEIR
PRESENT CLINICAL STATUS:
• The potential of nanomedicines as anticancer agents is being studied.
Treatments to enhance medication delivery, boost therapeutic efficacy,
lessen side effects, and beat drug resistance.
• Various articles published on the subjects of "nanomedicine,"
"nanoscience," and "nanotechnology" has grown dramatically during
the previous ten years with a little dip in 2012.
• The current state of our understanding of nanoparticles emphasizes
safety and effectiveness.
• There are main 5 types of nanoparticles that are used in the treatment
of cancer. These are given below:
1. Lipid-based nanoparticles
2. Polymer-based nanoparticles and micelles
3. Dendrimers
4. Carbon-based Nanoparticles
5. Metallic and magnetic nanoparticles 14

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